Gene Summary

Gene:SIX1; SIX homeobox 1
Aliases: BOS3, TIP39, DFNA23
Summary:The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein SIX1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (49)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Mutation
  • Protein Tyrosine Phosphatases
  • Gene Expression Profiling
  • Apoptosis
  • Carcinogenesis
  • Wilms Tumour
  • Down-Regulation
  • Cancer Gene Expression Regulation
  • Homeodomain Proteins
  • Gene Expression
  • Eye Proteins
  • Neoplasm Metastasis
  • Cell Movement
  • Intracellular Signaling Peptides and Proteins
  • siRNA
  • HEK293 Cells
  • Cervical Cancer
  • Transcription Factor AP-1
  • Epithelial-Mesenchymal Transition
  • Messenger RNA
  • Biomarkers, Tumor
  • Immunohistochemistry
  • Epithelium
  • Cell Proliferation
  • Nuclear Proteins
  • Chromosome 14
  • Homeobox Genes
  • Signal Transduction
  • Neoplastic Cell Transformation
  • Disease Progression
  • MicroRNAs
  • Oligonucleotide Array Sequence Analysis
  • Nerve Tissue Proteins
  • Neoplasm Invasiveness
  • Cell Cycle
  • Breast Cancer
  • RNA Interference
  • 3' Untranslated Regions
  • Western Blotting
  • Transforming Growth Factor beta
  • Hepatocellular Carcinoma
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SIX1 (cancer-related)

Chu Y, Chen Y, Li M, et al.
Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia.
Cancer Sci. 2019; 110(7):2200-2210 [PubMed] Free Access to Full Article Related Publications
Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c-Kit

Wan J, Yang J, Qiao C, et al.
MicroRNA-362 Inhibits Cell Proliferation and Invasion by Directly Targeting SIX1 in Colorectal Cancer.
Yonsei Med J. 2019; 60(5):414-422 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Colorectal cancer (CRC) is the third most common cancer in China and poses high morbidity and mortality. In recent years, increasing evidence has indicated that microRNAs played important functions in the occurrence and development of tumors. The purpose of this study was to identify the biological mechanisms of miR-362 in CRC.
MATERIALS AND METHODS: Quantitative real-time PCR was carried out to assess the expression of miR-362 and SIX1. The Kaplan-Meier method was employed to evaluate the 5-year overall survival of CRC patients. The proliferative and invasive abilities of CRC cells were assessed by MTT and transwell assays.
RESULTS: miR-362 was significantly decreased in CRC tissues and cell lines, compared to the normal tissues and normal cells. A significant connection was confirmed between the overall survival of 53 CRC patients and low expression of miR-362. Downregulation of miR-362 inhibited the proliferation and invasion through binding to the 3'-UTR of SIX1 mRNA in CRC. Additionally, we discovered that SIX1 was a direct target gene of miR-362 and that the expression of miR-362 had a negative connection with SIX1 expression in CRC. SIX1 could reverse partial functions in the proliferation and invasion in CRC cells.
CONCLUSION: miR-362 may be a prognostic marker in CRC and suppress CRC cell proliferation and invasion in part through targeting the 3'-UTR of SIX1 mRNA. The newly identified miR-362/SIX1 axis provides insight into the progression of CRC.

D'Almeida O, Mothar O, Bondzie EA, et al.
Encapsulated miR-200c and Nkx2.1 in a nuclear/mitochondria transcriptional regulatory network of non-metastatic and metastatic lung cancer cells.
BMC Cancer. 2019; 19(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs are noncoding RNA molecules of ~ 22 nucleotides with diagnostic and therapeutic action [Curr Drug Targets, 2015. 16(12): p. 1381-403], affecting the expression of mRNAs involved in invasion, migration, and development [Oncotarget, 2015. 6(9): p. 6472-98, Cancer Manag Res, 2014. 6: p. 205-16]. miR-200c is part of the miR-200c/141 cluster on chromosome 12p13. Its mechanism of action when encapsulated is critical in lung cancer when patients express changes in miRNAs. miR-200c be a potential biomarkers for various lung diseases. As a potential therapy, miR-200c can impacts lives as target lung cancer is a leading cause of death with about 234,000 cases annually, high heterogeneity, complex screening, and a 5-year survival rate of 16% [CA Cancer J Clin, 2016.66(1): p. 7-30]. Encapsulated miR-200c efficiently enhances bioavailability, pharmacokinetics of therapeutics and targeting to cells, improves efficacy and provides potential cure.
METHODS: The functions of miR-200c were determined in non-metastatic KW-634 and metastatic 821-T4 and 821-LN mouse lung cancer cell lines after various Nano vehicle treatments. Viability and cytotoxicity were determined by cell cycle and quantitative real-time PCR analyses were used to quantify levels of miR-200c and its target genes. In situ hybridization was used to visualize patterns of expression of miR-200c and others in the lung and many organs. Next-generation sequencing accession number GSE125000, invasion and migration assays using transwell chambers, and ActivSignal were used to elucidate the activation and inhibition profiles and perform direct expression measurements and modification of cellular components.
RESULTS: Due to their effectiveness as intracellular vesicles transporting miR-200c into, out, and between parts of the cells, miR-200c is encapsulated with cholesterol, an integral part of the biological membranes with very important physical properties of the vehicle. Nano miR-200c showed efficient cellular uptake in KW-634, 821-T4, and 821-LN cells with important changes in gene expression and new isoforms. In KW-634, when treated with encapsulated miR-200c and compare to the non-encapsulated control; miR-29b increased by 5261-fold, and in 821-T4/LN, miR-1247 increased by 150-fold. Conversely, miR-1247 and miR-675 decreased by 348 and 1029.5-fold, respectively. miR-189 decreased by 34-fold in treated 821-T4 cells. A reduction of growth was observed only after 48 h of treatment with Nano miR-200c. Moreover, labeling the vehicle with carboxy-fluorescein showed that the encapsulated particles enter the nucleus and mitochondria. Encapsulated miR-200c by entering the cells, the nucleus and mitochondria, trigger changes in cell cycle phases with 4 up to 12 fold percentage in G2 and S phase respectively compare to miR-200c. Endogenous expression of Nkx2.1, miR-200c, and their targets Myb, Nfib, Six4 and Six1 showed an inverse correlation, as observed in development.
CONCLUSIONS: Little is known about miR-200c involvement in regulatory processes. Nano miR-200c affects invasion and migration mechanisms. The expression of encapsulated miR-200c contributes to the inhibition/activation of Kras, EMT, Hippo, regulatory pathways and blockers of metastasis. Delivery of miR-200c increases the expression of miR-29b, an EMY regulator, and miR-1247, an inhibitor of cancer genes, both tumor suppressors involved in lung metastasis. Encapsulated miR-200c act on different proteins that regulates cell cycle pathways. These findings represent a part of a regulatory network providing new insights towards improvement of therapy.

Song W, Ma J, Lei B, et al.
Sine oculis homeobox 1 promotes proliferation and migration of human colorectal cancer cells through activation of Wnt/β-catenin signaling.
Cancer Sci. 2019; 110(2):608-616 [PubMed] Free Access to Full Article Related Publications
Sine oculis homeobox 1 (Six1) is a homeodomain transcription factor that is aberrantly expressed in a variety of human cancers, including colorectal cancer (CRC). Six1 has been reported to play a key role in the proliferation and migration of CRC cells but the underlying molecular mechanisms are still poorly characterized. In the present study, we found that Six1 overexpression promoted the proliferation and migration of CRC cells. Consistently, Six1 knockdown (KD) significantly inhibited proliferation and migration of CRC cells. In addition, we showed that Six1 promoted proliferation and migration of CRC cells through activation of Wnt/β-catenin signaling, as evidenced by promotion of nuclear localization of β-catenin. Silencing of β-catenin expression with siRNA or inhibiting Wnt signaling with a specific inhibitor, xav939, significantly blocked Six1-induced nuclear localization of β-catenin and mitigated Six1-promoted proliferation and migration of CRC cells. We further confirmed the involvement of β-catenin in Six1-promoted proliferation and migration of CRC cells by activation of Wnt signaling with lithium chloride (LiCl) in Six1 KD CRC cells and results showed that LiCl restores defective β-catenin nuclear localization and proliferation and migration of CRC cells. Taken together, these results suggest that Six1 homeoprotein promotes the proliferation and migration of CRC cells by activating the Wnt/β-catenin signaling pathway, and strategies targeting Six1 may be promising for the treatment of CRC.

Zhang LS, Kang X, Lu J, et al.
Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.
EBioMedicine. 2019; 39:145-158 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/β-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear.
METHODS: We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs).
FINDINGS: We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/β-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML.
INTERPRETATION: By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.

Liu H, Wei W, Wang X, et al.
miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1.
Mol Med Rep. 2018; 18(6):5683-5692 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant bone tumor and the third most common cancer that occurs during childhood and adolescence. Increasing evidence has suggested that microRNA (miR)‑23b‑3p has an important role in OS tumorigenesis; however, the underlying molecular mechanisms remain unknown. The aim of the present study was to investigate the expression levels of miR‑23b‑3p and sine oculis homeobox homolog 1 (SIX1) in OS tissues and cell lines (MG‑63, SaOS‑2 and U2OS), as well as to observe the effects of miR‑23b‑3p on U2OS cell viability, cell cycle, apoptosis and invasive ability. The results revealed that the expression levels of miR‑23b‑3p were significantly decreased in OS tissues and cell lines compared with tumor‑adjacent normal tissues and a non‑cancerous human fetal osteoblastic cell line (hFOB1.19). To investigate the underlying mechanisms of miR‑23b‑3p in OS tumorigenesis and progression, human U2OS cell lines over‑ or under expressing miR‑23b‑3p were established. The effects of miR‑23b‑3p on U2OS cell viability, cell cycle, apoptosis and invasion properties were determined by performing Cell Counting Kit‑8, flow cytometry and Transwell invasion assays. miR‑23b‑3p was revealed to suppress cell viability, proliferation and invasion, and to enhance the levels of cell apoptosis. Furthermore, SIX1 mRNA and protein expression levels in OS tissues and cell lines were significantly upregulated when compared with tumor‑adjacent normal tissues and hFOB 1.19 cells, which suggested that SIX1 expression levels may be inversely associated with miR‑23b‑3p levels in OS. Luciferase reporter system analysis demonstrated that miR‑23b‑3p binds to the SIX1 3'‑untranslated region. miR‑23b‑3p downregulation contributed to SIX1 upregulation, which facilitated the potentiation of cyclin D1 and vascular endothelial growth factor‑C expression levels, as well as the inhibition of caspase‑3 expression. Collectively, these results suggested that miR‑23b‑3p is downregulated and SIX1 is upregulated in OS cells, and that miR‑23b‑3p inhibition may suppress the proliferation and invasion of OS cells, and contribute to cell apoptosis via negative regulation of SIX1. miR‑23b‑3p/SIX1 may therefore represent a potential target for the treatment of OS.

Xie Y, Jin P, Sun X, et al.
SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial-mesenchymal transition.
Cell Biochem Funct. 2018; 36(8):413-419 [PubMed] Related Publications
Sine oculis homeobox homologue 1 (SIX1) is a Six class homeobox gene conserved throughout many species. It has been reported to act as an oncogene and is overexpressed in many cancers. However, the function and regulatory mechanism of SIX1 in gastric cancer (GC) remains unclear. In our study, we detected protein levels of SIX1 via immunohistochemistry (IHC) and its proliferation and invasion effects via CCK8 and transwell assays. Additionally, expression of cyclin D1, MMP2, p-ERK, and EMT-related proteins was measured by western blotting. We found that SIX1 had significantly higher expression in GC tissues and that it could promote GC cell proliferation and invasion. Also, overexpression of SIX1 increased the expression of cyclin D1, MMP2, p-ERK, and EMT-related proteins, which could all be inhibited by knocking down SIX1. In conclusion, SIX1 is upregulated in GC tissues. It can promote GC cell proliferation by targeting cyclin D1, invasion via ERK signalling, and EMT pathways by targeting MMP2 and E-cadherin. SIGNIFICANCE OF THE STUDY: Our study showed that SIX1 was upregulated in GC tissues, and promoted GC cell proliferation by targeting cyclin D1, invasion via ERK signalling, and EMT pathways by targeting MMP2 and E-cadherin. These results suggested the potential regulatory mechanism of SIX1 in proliferation and invasion of gastric cancer.

Zhong L, Sun S, Yao S, et al.
Histone deacetylase 5 promotes the proliferation and invasion of lung cancer cells.
Oncol Rep. 2018; 40(4):2224-2232 [PubMed] Related Publications
Histone deacetylase 5 (HDAC5), as a member of the class IIa family of HDACs, is frequently dysregulated in human malignancies. However, little is known regarding the specific role of HDAC5 in lung cancer. We aimed to evaluate HDAC5 expression in human lung cancer and to determine the effects of HDAC5 on lung cancer cells. First, the expression levels of both HDAC5 protein and mRNA were evaluated in lung cancer tissues and cell lines by western blot analysis and RT‑qPCR, and the results suggested that HDAC5 was significantly upregulated in human lung cancer tissues and cell lines. To address the effects of HDAC5 on the biological behavior of human lung adenocarcinoma cells, we generated human lung cancer A549 cell lines in which HDAC5 was either overexpressed or depleted. The results indicated that overexpression of HDAC5 significantly promoted the proliferation and invasion, and inhibited the apoptosis of A549 cells. On the contrary, HDAC5 knockdown largely decreased the proliferation and invasion and enhanced the apoptosis of A549 cells. Furthermore, we demonstrated that HDAC5 overexpression promoted the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Downregulation of HDAC5 caused a significant inhibition of the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Taken together, our data demonstrated that HDAC5 displayed a significant upregulation in lung cancer, and elevated HDAC5 might be involved in the potentiation of proliferation and invasion of lung cancer cells, as well as the inhibition of lung cancer cell apoptosis by the upregulation of DLL4, Six1, Notch 1 and Twist 1. The present study may provide an evidence for the potential application of HDAC5 inhibitors in the therapy of lung cancer.

Yu C, Zhang B, Li YL, Yu XR
SIX1 reduces the expression of PTEN via activating PI3K/AKT signal to promote cell proliferation and tumorigenesis in osteosarcoma.
Biomed Pharmacother. 2018; 105:10-17 [PubMed] Related Publications
OBJECTIVE: Osteosarcoma is the most common form of primary malignant bone cancer which is most prevalent in children and adolescents. Dysregulated expressions of SIX1 and PTEN/PI3K/AKT have been demonstrated in bone malignancies including osteosarcoma. However, the mechanism of SIX1/PTEN/PI3K/AKT on osteosarcoma progression remains unknown. Therefore, this study aims to investigate the molecular mechanism of SIX1 and PTEN/PI3K/AKT on osteosarcoma progression.
METHODS: In this study, we first examined the expression of SIX1 and PTEN in human osteosarcoma tissues or blood samples and cell lines by immunohistochemistry, western blot analysis and qPCR. MTT, clone formation assay, wound healing assay, Transwell assay, in vivo tumorigenesis, flow cytometry and western blot were used to determine the function of SIX1/PTEN on cell proliferation, clone formation ability, migration, invasion, tumorigenesis, and cell apoptosis in SAOS2 and U2OS cells, respectively.
RESULTS: Results showed that SIX1 was overexpressed in osteosarcoma tissues, blood samples and cell lines, whereas PTEN expression was reduced. SIX1 promoted cell growth, migration, invasion, and suppressed cell apoptosis. Up-regulation of SIX1 associated with reduced expression of PTEN and activation of PI3K/AKT signaling pathway. Down-regulated the expression of PTEN using gene transfer in U2OS and SAOS2 cells increased cell proliferation and inhibited cell apoptosis through activating PI3K/AKT signaling cascade. In addition, the tumorigenesis of U2OS and SAOS2 cells was suppressed when the cells were stably overexpressed SIX1 and PTEN simultaneously, compared with that in cells stably overexpressed SIX1 only.
CONCLUSIONS: SIX1 promoted the progression of osteosarcoma via regulating PTEN/PI3K/AKT signaling cascade, which might provide a new potent therapeutic target for osteosarcoma.

Li B, Zhao S, Geng R, et al.
The Sineoculis Homeobox Homolog 1 (SIX1) Gene Regulates Paclitaxel Resistance by Affecting Reactive Oxygen Species and Autophagy in Human Hepatocellular Carcinoma Cell Line HepG2.
Med Sci Monit. 2018; 24:2271-2279 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The objective of this study was to explore the role of SIX1 in paclitaxel (TAX) resistance of HepG2 cells via reactive oxygen species (ROS) and autophagy pathway. MATERIAL AND METHODS Hepatoma cell line HepG2 was treated with SIX1 knockdown or/and TAX. Cell growth was detected by MTT assay and colony formation assay. Cell apoptosis was evaluated with flow cytometry. ROS levels were detected using flow cytometry (stained with DCFH2-DA). Western blot was conducted to detect the expression of SIX1 and autophagy-related proteins. RESULTS TAX suppressed the proliferation of HepG2 cells in a time/dose-dependent manner, and upregulated the expression of SIX1. SIX1 siRNA increased TAX sensitivity of HepG2 cells and upregulated cell ROS levels. SIX1 siRNA combined with TAX treatment activated autophagy of HepG2 cells. N-acetyl-L-cysteine (NAC) partially attenuated SIX1 siRNA-induced ROS level increases, and autophagy inhibitor 3-MA notably enhanced SIX1 siRNA-induced cell apoptosis. CONCLUSIONS Knockdown of SIX1 increased cell ROS levels and autophagy, promoted cell apoptosis, and enhanced TAX sensitivity of HepG2 cells.

Li L, Liang Y, Kang L, et al.
Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.
Cancer Cell. 2018; 33(3):368-385.e7 [PubMed] Related Publications
Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.

Cheng Q, Ning D, Chen J, et al.
SIX1 and DACH1 influence the proliferation and apoptosis of hepatocellular carcinoma through regulating p53.
Cancer Biol Ther. 2018; 19(5):381-390 [PubMed] Free Access to Full Article Related Publications
ABSTRACTS This research aimed to explore effects of SIX1 and DACH1 on hepatocellular carcinoma (HCC) cell proliferation, apoptosis and cell cycle. Fifty paired hepatocellular carcinoma tissues were screened for differentially expressed genes. SIX1 and DACH1 expressions were subjected to qRT-PCR and western blot in tumor tissues and cells. The knockdown efficiency of siRNAs and transfection efficiency of cDNAs and siRNAs were validated by qRT-PCR and western blot as well. Then colony formation assay and flow cytometry were applied to observe cell proliferation, cell apoptosis and cell cycle changes. Immunofluorescence co-localization and immunoprecipitation were used to analyze the interaction between proteins which was quantified using western blot. Effects of SIX1 and DACH1 on tumor growth and their expressions in tumors were confirmed in vitro in nude mice model. Results of these experiments showed that SIX1 was overexpressed while DACH1 was suppressed in HCC tissues and cells. The suppression of SIX1 and overexpression of DACH1 not only inhibited cell proliferation, but also induced cell apoptosis and arrested cell cycle in G2/M phase compared with control group. Results of immunofluorescence co-localization suggested that SIX1, p53 and DACH1 were significantly overlapped. Immunoprecipitation showed that DACH1 (marked with Flag tag) could pull down p53 and SIX1, but SIX1 (marked with His tag) could only pull down DACH1, which indicated that an indirect regulation between SIX1 and p53. Validated with western blot afterwards, DACH1 overexpression suppressed tumorigenesis in vivo by up-regulating p53 expression while SIX1 overexpression accelerated tumor growth by down-regulating p53 expression. Therefore, the decrease of SIX1 facilitated the expression of DACH1, thus activated the expression of p53 and suppressed the progression of HCC both in vitro and in vivo.

Wen Z, Liang C, Pan Q, Wang Y
Eya2 overexpression promotes the invasion of human astrocytoma through the regulation of ERK/MMP9 signaling.
Int J Mol Med. 2017; 40(5):1315-1322 [PubMed] Free Access to Full Article Related Publications
The overexpression of eyes absent (Eya) 2 has been found in several human cancers. However, its biological roles and clinical significance in human astrocytoma have not yet been explored. This study investigated the clinical significance and biological roles of Eya2 in human astrocytoma tissues and cell lines. Using immunohistochemistry, we found Eya2 overexpression in 33 out of 90 (36.7%) astrocytoma specimens. The rate of Eya2 overexpression was higher in grade III-IV (48.1%) than in grade Ⅰ+Ⅱ astrocytomas (21.1%). Transfection with an Eya2 expression plasmid was performed in A172 cells with a low endogenous expression of Eya2 and the knockdown of Eya2 was carried out in U251 cells with a high endogenous expression using siRNA. Eya2 overexpression induced A172 cell proliferation and invasion, while the knockdown of Eya2 using siRNA decreased the proliferation and invasion of U251 cells. In addition, we found that transfection with the Eya2 expression plasmid facilitated cell cycle progression, and that the knockdown of Eya2 inhibited cell cycle progression, accompanied by a change in the expression of cell cycle-related proteins, including cyclin D1 and cyclin E. Eya2 also positively regulated extracellular signal-regulated kinase (ERK) activity and matrix metalloproteinase (MMP)9 expression. The blockade of ERK signaling using an inhibitor abolished the effects of Eya2 on A172 cell invasion and MMP9 production. In addition, we found that there was a positive correlation between Eya2 and Six1 in the astrocytoma cell lines. Immunoprecipitation revealed that Eya2 interacted with Six1 protein in the U251 cell line, which exhibited a high expression of both proteins. Eya2 failed to upregulate MMP expression in the A172 cells in which Six1 was silenced. On the whole, our data indicate that Eya2 may serve as a potential oncoprotein in human astrocytoma. Eya2 regulates astrocytoma cell proliferation and invasion, possibly through the regulation of ERK signaling.

Gadd S, Huff V, Walz AL, et al.
A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.
Nat Genet. 2017; 49(10):1487-1494 [PubMed] Free Access to Full Article Related Publications
We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

Zhu Q, Li H, Li Y, Jiang L
MicroRNA-30a functions as tumor suppressor and inhibits the proliferation and invasion of prostate cancer cells by down-regulation of SIX1.
Hum Cell. 2017; 30(4):290-299 [PubMed] Free Access to Full Article Related Publications
Increasing reports have demonstrated that aberrant expression of microRNAs (miRNAs) is found in multiple human cancers. Many studies have shown that down-regulated level of miR-30a is in a variety of cancers including prostate cancer (PCa). However, the precise mechanisms of miR-30a in PCa have not been well explored. In this study, we investigated the biological functions and molecular mechanism of miR-30a in PCa cell lines, discussing whether it could be a therapeutic biomarker of PCa in the future. We found that miR-30a is down-regulated in PCa tissues and cell lines. Moreover, the low level of miR-30a was associated with increased expression of SIX1 in PCa tissues and cell lines. Up-regulation of miR-30a significantly inhibited proliferation of PCa cells. In addition, invasion of PCa cells was suppressed by overexpression of miR-30a. However, down-regulation of miR-30a promoted cell growth and invasion of PCa cells. Bioinformatics analysis predicted that the SIX1 was a potential target gene of miR-30a. Next, luciferase reporter assay confirmed that miR-30a could directly target SIX1. Consistent with the effect of miR-30a, down-regulation of SIX1 by siRNA inhibited proliferation and invasion of PCa cells. Overexpression of SIX1 in PCa cells partially reversed the effect of miR-30a mimic. In conclusion, introduction of miR-30a dramatically inhibited proliferation and invasion of PCa cells by down-regulating SIX1 expression, and that down-regulation of SIX1 was essential for inhibition of cell growth and invasion of PCa cells by overexpression of miR-30a.

Lerbs T, Bisht S, Schölch S, et al.
Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer.
BMC Cancer. 2017; 17(1):249 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Assessment of transcription factors involved in these two mechanisms can help to identify new targets for an oncological therapy. In this study, we focused on the evaluation of the transcription factor Six1 (Sine oculis 1). This protein is involved in embryologic development and its contribution to carcinogenesis has been described in several studies.
METHODS: Immunohistochemistry against Six1 was performed on a tissue microarray containing specimens of primary pancreatic ductal adenocarcinomas (PDAC) of 139 patients. Nuclear and cytoplasmic expression was evaluated and correlated to histopathological parameters. Expression of Six1 was inhibited transiently by siRNA in Panc1 and BxPc3 cells and stably by shRNA in Panc1 cells. Expression analysis of CDH1 and Vimentin mRNA was performed and cell motility was tested in a migration assay. Panc1 cells transfected with Six1 shRNA or scrambled shRNA were injected subcutaneously into nude mice. Tumour growth was observed for four weeks. Afterwards, tumours were stained against Six1, CD24 and CD44.
RESULTS: Six1 was overexpressed in the cytoplasm and cellular nuclei in malignant tissues (p < 0.0001). No correlation to histopathological parameters could be detected. Six1 down-regulation decreased pancreatic cancer cell motility in vitro. CDH1 and vimentin expression was decreased after inhibition of the expression of Six1. Pancreatic tumours with impaired expression of Six1 showed significantly delayed growth and displayed loss of the CD24
CONCLUSION: We show that Six1 is overexpressed in human PDAC and that its inhibition results in a decreased tumour progression in vitro and in vivo. Therefore, targeting Six1 might be a novel therapeutic approach in patients with pancreatic cancer.

Shi C, Zhang Z
MicroRNA-362 is downregulated in cervical cancer and inhibits cell proliferation, migration and invasion by directly targeting SIX1.
Oncol Rep. 2017; 37(1):501-509 [PubMed] Related Publications
Cervical cancer is the second most common type of cancer in women accounting for 12% of all human cancers in the world. Mounting evidence demonstrates that microRNAs play important roles in the carcinogenesis and progression of cervical cancer. The aim of this study was to investigate the expression, roles and molecular mechanism of microRNA-362 (miR-362) in cervical cancer. According to the results, we found that expression level of miR-362 was significantly reduced in cervical cancer tissues and cell lines. Low miR-362 expression was correlated with FIGO stage, lymph node metastasis and vascular invasion in cervical cancer. Functional assays showed that restoration of miR-362 repressed cell proliferation, migration and invasion in cervical cancer. We also provided direct evidence that sineoculis homeobox homolog 1 (SIX1) was a direct target of miR-362 in cervical cancer, which was confirmed by bioinformatics analysis, luciferase reporter assay, qRT-PCR and western blot analysis. SIX1 was upregulated in cervical cancer and inversely correlated with miR‑362 expression in cervical cancer. In addition, SIX1 knockdown could simulate the roles of miR-362 overexpression on cell proliferation, migration and invasion of cervical cancer. Moreover, rescue experiments indicated that restoration of SIX1 was sufficient to abolish proliferation, migration and invasion induced by miR-362 overexpression in cervical cancer cells. The newly identified miR-362/SIX1 pathway provides insight into cervical cancer progression, and may represent a novel therapeutic target.

Liu Q, Li A, Tian Y, et al.
The expression profile and clinic significance of the SIX family in non-small cell lung cancer.
J Hematol Oncol. 2016; 9(1):119 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The SIX family homeobox genes have been demonstrated to be involved in the tumor initiation and progression, but their clinicopathological features and prognostic values in non-small cell lung cancer (NSCLC) have not been well defined. We analyzed relevant datasets and performed a systemic review and a meta-analysis to assess the profile of SIX family members in NSCLC and evaluate their importance as biomarkers for diagnosis and prediction of NSCLC.
METHODS: This meta-analysis included 17 studies with 2358 patients. Hazard ratio (HR) and 95 % confidence interval (CI) were calculated to represent the prognosis of NSCLC with expression of the SIX family genes. Heterogeneity of the ORs and HRs was assessed and quantified using the Cochrane Q and I
RESULTS: The systematic meta-analysis unveiled that the higher expressions of SIX1-5 were associated with the greater possibility of the tumorigenesis. SIX4 and SIX6 were linked to the lymph node metastasis (LNM). SIX2, SIX3, and SIX4 were correlated with higher TNM stages. Furthermore, the elevated expressions of SIX2, SIX4, and SIX6 predicted poor overall survival (OS) in NSCLC (SIX2: HR = 1.14, 95 % CI, 1.00-1.31; SIX4: HR = 1.39, 95 % CI, 1.16-1.66; SIX6: HR = 1.18, 95 % CI, 1.00-1.38) and poor relapse-free survival (RFS) in lung adenocarcinoma (ADC) (SIX2: HR = 1.42, 95 % CI, 1.14-1.77; SIX4: HR = 1.52, 95 % CI, 1.09-2.11; SIX6: HR = 1.25, 95 % CI, 1.01-1.56).
CONCLUSIONS: Our report demonstrated that the SIX family members play distinct roles in the tumorigenesis of NSCLC and can be potential biomarkers in predicting prognosis of NSCLC patients.

Xu HX, Wu KJ, Tian YJ, et al.
Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis.
Medicine (Baltimore). 2016; 95(27):e4085 [PubMed] Free Access to Full Article Related Publications
Sineoculis homeobox homolog (SIX) family proteins, including SIX1, SIX2, SIX3, SIX4, SIX5, and SIX6, have been implicated in the initiation and progression of breast cancer, but the role of each member in breast tumor is not fully understood. We conducted a systematic review and meta-analysis to evaluate the association between the mRNA levels of all 6 members and clinic-pathological characteristics and clinical outcome of breast cancer patients based on the PRISMA statement criteria.ArrayExpress and Oncomine were searched for eligible databases published up to December 10, 2015. The association between the mRNA expression of SIX family members and clinic-pathological features and prognosis was measured by the odds ratio (OR), hazard ratio (HR), and the corresponding 95% confidence interval (CI), respectively. All statistical analyses were performed using STATA software.In total, 20 published Gene Expression Omnibus (GEO) databases with 3555 patients were analyzed. Our analysis revealed that patients with SIX1 overexpression had worse overall survival (OS) (HR: 1.28, 95% CI: 1.03-1.58) and shorter relapse-free survival (RFS) (HR: 1.28, 95% CI: 1.05-1.56), and much worse prognosis for luminal breast cancer patients with SIX1 overexpression (OS: HR: 1.64, 95% CI: 1.13-2.39; RFS: HR: 1.43, 95% CI: 1.06-1.93). We found that patients with higher SIX2 level had shorter time to both relapse and metastasis. However, high SIX3 mRNA level was a protective factor for OS and RFS of basal-like breast cancer patients.Our study suggested that members of SIX family played distinct roles in breast cancer. Detailed analysis of the expression of the SIX family members might provide useful information to predict breast cancer progression and prognosis.

Brandt A, Löhers K, Beier M, et al.
Establishment of a Conditionally Immortalized Wilms Tumor Cell Line with a Homozygous WT1 Deletion within a Heterozygous 11p13 Deletion and UPD Limited to 11p15.
PLoS One. 2016; 11(5):e0155561 [PubMed] Free Access to Full Article Related Publications
We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD) limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD) 3p21.3pter lead to the homozygous CTNNB1 mutation. The tumor cell line was immortalized using the catalytic subunit of human telomerase (hTERT) in conjunction with a novel thermolabile mutant (U19dl89-97tsA58) of SV40 large T antigen (LT). This cell line is cytogenetically stable and can be grown indefinitely representing a valuable tool to study the effect of a complete lack of WT1 in tumor cells. The origin/fate of Wilms tumors with WT1 mutations is currently poorly defined. Here we studied the expression of several genes expressed in early kidney development, e.g. FOXD1, PAX3, SIX1, OSR1, OSR2 and MEIS1 and show that these are expressed at similar levels in the parental and the immortalized Wilms10 cells. In addition the limited potential for muscle/ osteogenic/ adipogenic differentiation similar to all other WT1 mutant cell lines is also observed in the Wilms10 tumor cell line and this is retained in the immortalized cells. In summary these Wilms10 cells are a valuable model system for functional studies of WT1 mutant cells.

Kong D, Liu Y, Liu Q, et al.
The retinal determination gene network: from developmental regulator to cancer therapeutic target.
Oncotarget. 2016; 7(31):50755-50765 [PubMed] Free Access to Full Article Related Publications
Although originally identified for its function in Drosophila melanogaster eye specification, the Retinal Determination Gene Network (RDGN) is essential for the development of multiple organs in mammals. The RDGN regulates proliferation, differentiation and autocrine signaling, and interacts with other key signaling pathways. Aberrant expression of RDGN members such as DACH, EYA and SIX contributes to tumor initiation and progression; indeed, the levels of RDGN members are clinically prognostic factors in various cancer types. Stimulation or suppression of the activities of these crucial components can block cancer cell proliferation, prevent cancer stem cell expansion and even reverse the EMT process, thereby attenuating malignant phenotypes. Thus, cancer therapeutic interventions targeting RDGN members should be pursued in future studies.

Armat M, Ramezani F, Molavi O, et al.
Six family of homeobox genes and related mechanisms in tumorigenesis protocols.
Tumori. 2016; 2016(3):236-43 [PubMed] Related Publications
In recent years, the homeobox gene superfamily has been introduced as a master regulator in downstream target genes related to cell development and proliferation. An indispensable role of this family involved in organogenesis development has been widely demonstrated since expression of Six family led to a distinct increase in development of various organs. These functions of Six family genes are primarily based on structure as well as regulatory role in response to external or internal stimuli. In addition to these roles, mutation or aberrant expression of Six family plays a fundamental role in initiation of carcinogenesis, a multistep process including transformation, proliferation, angiogenesis, migration, and metastasis. This suggests that the Six superfamily members can be considered as novel target molecules to inhibit tumor growth and progression. This review focuses on the structure, function, and mechanisms of the Six family in cancer processes and possible strategies to apply these family members for diagnostic, prognostic, and therapeutic purposes.

Spreafico F, Ciceri S, Gamba B, et al.
Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences.
Oncotarget. 2016; 7(8):8908-15 [PubMed] Free Access to Full Article Related Publications
Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures. Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.

Armat M, Oghabi Bakhshaiesh T, Sabzichi M, et al.
The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line.
Bosn J Basic Med Sci. 2016; 16(1):28-34 [PubMed] Free Access to Full Article Related Publications
The resistance of cancer cells to chemotherapeutic agents represents the main problem in cancer treatment. Despite intensive research, mechanisms of resistance have not yet been fully elucidated. Six1 signaling has an important role in the expansion of progenitor cell populations during early embryogenesis. Six1 gene overexpression has been strongly associated with aggressiveness, invasiveness, and poor prognosis of different cancers. In this study, we investigated the role of Six1 signaling in resistance of MCF-7 breast cancer cells to taxanes. We first established in vitro paclitaxel-resistant MCF-7 breast cancer cells. Morphological modifications in paclitaxel-resistant cells were examined via light microscopic images and fluorescence-activated cell sorting analysis. Applying quantitative real-time polymerase chain reaction, we measured Six1, B-cell lymphoma/leukemia(BCL-2), BAX, and P53 mRNA expression levels in both non-resistant and resistant cells. Resistant cells were developed from the parent MCF-7 cells by applying increasing concentrations of paclitaxel up to 64 nM. The inhibitory concentration 50% value in resistant cells increased from 3.5 ± 0.03 to 511 ± 10.22 nM (p = 0.015). In paclitaxel-resistant cells, there was a significant increase in Six1 and BCL-2 mRNA levels (p = 0.0007) with a marked decrease in pro-apoptotic Bax mRNA expression level (p = 0.03); however, there was no significant change in P53 expression (p = 0.025). Our results suggest that identifying cancer patients with high Six1 expression and then inhibition of Six1 signaling can improve the efficiency of chemotherapeutic agents in the induction of apoptosis.

Towers CG, Guarnieri AL, Micalizzi DS, et al.
The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.
Nat Commun. 2015; 6:10077 [PubMed] Free Access to Full Article Related Publications
TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

Adrados I, Larrasa-Alonso J, Galarreta A, et al.
The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes.
Oncogene. 2016; 35(27):3485-94 [PubMed] Free Access to Full Article Related Publications
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis.

Zakrzewski K, Jarząb M, Pfeifer A, et al.
Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features.
BMC Cancer. 2015; 15:778 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pilocytic astrocytoma is the most common type of brain tumor in the pediatric population, with a generally favorable prognosis, although recurrences or leptomeningeal dissemination are sometimes also observed. For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features, and the clinical pattern of the disease.
METHODS: Eighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in this study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples).
RESULTS: Bioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression.
CONCLUSIONS: Here we have shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease.

Wang L, Liu H
microRNA-188 is downregulated in oral squamous cell carcinoma and inhibits proliferation and invasion by targeting SIX1.
Tumour Biol. 2016; 37(3):4105-13 [PubMed] Related Publications
microRNA-188 expression is downregulated in several tumors. However, its function and mechanism in human oral squamous cell carcinoma (OSCC) remains obscure. The present study aims to identify the expression pattern, biological roles, and potential mechanism by which miR-188 dysregulation is associated with oral squamous cell carcinoma. Significant downregulation of miR-188 was observed in OSCC tissues compared with paired normal tissues. In vitro, gain-of-function, loss-of-function experiments were performed to examine the impact of miR-188 on cancer cell proliferation, invasion, and cell cycle progression. Transfection of miR-188 mimics suppressed Detroit 562 cell proliferation, cell cycle progression and invasion, with downregulation of cyclin D1, MMP9, and p-ERK. Transfection of miR-188 inhibitor in FaDu cell line with high endogenous expression exhibited the opposite effects. Using fluorescence reporter assays, we confirmed that SIX1 was a direct target of miR-188 in OSCC cells. Transfection of miR-188 mimics downregulated SIX1 expression. SIX1 siRNA treatment abrogated miR-188 inhibitor-induced cyclin D1 and MMP9 upregulation. In addition, we found that SIX1 was overexpressed in 32 of 80 OSCC tissues. In conclusion, this study indicates that miR-188 downregulation might be associated with oral squamous cell carcinoma progression. miR-188 suppresses proliferation and invasion by targeting SIX1 in oral squamous cell carcinoma cells.

Nagel S, Meyer C, Kaufmann M, et al.
Aberrant expression of homeobox gene SIX1 in Hodgkin lymphoma.
Oncotarget. 2015; 6(37):40112-26 [PubMed] Free Access to Full Article Related Publications
In Hodgkin lymphoma (HL) we recently identified deregulated expression of homeobox genes MSX1 and OTX2 which are physiologically involved in development of the embryonal neural plate border region. Here, we examined in HL homeobox gene SIX1 an additional regulator of this embryonal region mediating differentiation of placodal precursors. SIX1 was aberrantly activated in 12 % of HL patient samples in silico, indicating a pathological role in a subset of this B-cell malignancy. In addition, SIX1 expression was detected in HL cell lines which were used as models to reveal upstream factors and target genes of this basic developmental regulator. We detected increased copy numbers of the SIX1 locus at chromosome 14q23 correlating with enhanced expression while chromosomal translocations were absent. Moreover, comparative expression profiling data and pertinent gene modulation experiments indicated that the WNT-signalling pathway and transcription factor MEF2C regulate SIX1 expression. Genes encoding the transcription factors GATA2, GATA3, MSX1 and SPIB - all basic lymphoid regulators - were identified as targets of SIX1 in HL. In addition, cofactors EYA1 and TLE4, respectively, contrastingly mediated activation and suppression of SIX1 target gene expression. Thus, the protein domain interfaces may represent therapeutic targets in SIX1-positive HL subsets. Collectively, our data reveal a gene regulatory network with SIX1 centrally deregulating lymphoid differentiation and support concordance of lymphopoiesis/lymphomagenesis and developmental processes in the neural plate border region.

Zeng J, Wei M, Shi R, et al.
MiR-204-5p/Six1 feedback loop promotes epithelial-mesenchymal transition in breast cancer.
Tumour Biol. 2016; 37(2):2729-35 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is a vital process in epithelial cancer invasion and metastasis. The induction of EMT by Six1 has been described as a common mode of cancer progression, which could promote breast cancer migration and invasion. In the study, we found that miR-204-5p could suppress the migration and invasion of breast cancer cell lines. Since overexpression of Six1 promote EMT, we identified a mechanism by which miR-204-5p inhibited the EMT by downregulating the Six1, which was mediated by a conserved miR-204-5p seed-matching sequence in the 3'-UTR of Six1 mRNA. We also identified that upregulation of Six1 could downregulate miR-204-5p expression, affecting the migration and invasion of breast cancer cell lines. In conclusion, the frequent upregulation of Six1 and/or downregulation of miR-204-5p in breast cancer may shift the equilibrium of these reciprocal regulations and lock breast cancer cells in the mesenchymal state.

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