SOX15 and other SOX family members are important mediators of tumorigenesis in multiple cancer types

SOX genes are transcription factors with important roles in embryonic development and carcinogenesis. The SOX family of 20 genes is responsible for regulating lineage and tissue specific gene expression patterns, controlling numerous developmental processes including cell differentiation, sex determination, and organogenesis. As is the case with many genes involved in regulating development, SOX genes are frequently deregulated in cancer. In this perspective we provide a brief overview of how SOX proteins can promote or suppress cancer growth. We also present a pan-cancer analysis of aberrant SOX gene expression and highlight potential molecular mechanisms responsible for their disruption in cancer. Our analyses indicate the prominence of SOX deregulation in different cancer types and reveal potential roles for SOX genes not previously described in cancer. Finally, we summarize our recent identification of SOX15 as a candidate tumor suppressor in pancreatic cancer and propose several research avenues to pursue to further delineate the emerging role of SOX15 in development and carcinogenesis.

[1]  I. Yeh,et al.  SOX‐10 expression in cutaneous myoepitheliomas and mixed tumors , 2014, Journal of cutaneous pathology.

[2]  Guangchao Sui,et al.  SOX7: from a developmental regulator to an emerging tumor suppressor. , 2014, Histology and histopathology.

[3]  Jing Wu,et al.  Oncogenicity of the transcription factor SOX8 in hepatocellular carcinoma , 2014, Medical Oncology.

[4]  W. Lam,et al.  SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling , 2014, Oncogene.

[5]  W. Park,et al.  Aberrant expression of SOX9 is associated with gastrokine 1 inactivation in gastric cancers , 2014, Gastric Cancer.

[6]  L. Miller,et al.  The regulation of SOX7 and its tumor suppressive role in breast cancer. , 2013, The American journal of pathology.

[7]  M. Corada,et al.  Sox17 is indispensable for acquisition and maintenance of arterial identity , 2013, Nature Communications.

[8]  H. Kondoh,et al.  Sox proteins: regulators of cell fate specification and differentiation , 2013, Development.

[9]  Y. Shih,et al.  SOX1 suppresses cell growth and invasion in cervical cancer. , 2013, Gynecologic oncology.

[10]  R. Boxtel,et al.  The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? , 2013, Oncogene.

[11]  N. Ordóñez Value of SOX10 Immunostaining in Tumor Diagnosis , 2013, Advances in anatomic pathology.

[12]  S. Mori,et al.  SOX7 is down-regulated in lung cancer , 2013, Journal of experimental & clinical cancer research : CR.

[13]  E. Campo,et al.  SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. , 2013, Blood.

[14]  D. Parkinson,et al.  Expression of c‐Jun and Sox‐2 in human schwannomas and traumatic neuromas , 2013, Histopathology.

[15]  K. Hochedlinger,et al.  The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. , 2013, Cell stem cell.

[16]  Mary Goldman,et al.  The UCSC Cancer Genomics Browser: update 2015 , 2014, Nucleic Acids Res..

[17]  B. Christensen,et al.  Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation , 2012, PloS one.

[18]  R. Moon,et al.  WNT signalling pathways as therapeutic targets in cancer , 2012, Nature Reviews Cancer.

[19]  Alexander van Oudenaarden,et al.  Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning. , 2012, Genes & development.

[20]  K. Jensen,et al.  Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[21]  Xiaoming Liu,et al.  The Role of Sox Genes in Lung Morphogenesis and Cancer , 2012, International journal of molecular sciences.

[22]  J. Ericson,et al.  Mechanistic differences in the transcriptional interpretation of local and long-range Shh morphogen signaling. , 2012, Developmental cell.

[23]  Robert Gentleman,et al.  Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer , 2012, Nature Genetics.

[24]  R. Buckanovich,et al.  Ovarian cancer stem cell markers: prognostic and therapeutic implications. , 2012, Cancer letters.

[25]  A. Rizzino,et al.  Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells , 2012, PloS one.

[26]  M. Sanchez-Cespedes,et al.  The SOX family of genes in cancer development: biological relevance and opportunities for therapy , 2012, Expert opinion on therapeutic targets.

[27]  B. Li,et al.  Decreased Expression of SOX7 is Correlated with Poor Prognosis in Lung Adenocarcinoma Patients , 2012, Pathology & Oncology Research.

[28]  J. Herman,et al.  SOX17 methylation inhibits its antagonism of Wnt signaling pathway in lung cancer. , 2012, Discovery medicine.

[29]  Aftab Ahmad,et al.  Expression of Sox2 and Oct4 and Their Clinical Significance in Human Non-Small-Cell Lung Cancer , 2012, International journal of molecular sciences.

[30]  Jun Yuan,et al.  Oncogenic role of SOX9 expression in human malignant glioma , 2012, Medical Oncology.

[31]  P. Northcott,et al.  Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. , 2012, Cancer cell.

[32]  Na Li,et al.  SOX2 Gene Regulates the Transcriptional Network of Oncogenes and Affects Tumorigenesis of Human Lung Cancer Cells , 2012, PloS one.

[33]  L. Zou,et al.  Expression features of SOX9 associate with tumor progression and poor prognosis of hepatocellular carcinoma , 2012, Diagnostic Pathology.

[34]  Paul Polakis,et al.  Wnt signaling in cancer. , 2012, Cold Spring Harbor perspectives in biology.

[35]  Manuel Serrano,et al.  Oncogenicity of the developmental transcription factor Sox9. , 2012, Cancer research.

[36]  M. Fukayama,et al.  SOX9 expression and its methylation status in gastric cancer , 2012, Virchows Archiv.

[37]  S. Yousem Role of molecular studies in the diagnosis of lung adenocarcinoma , 2012, Modern Pathology.

[38]  R. Lovell-Badge,et al.  Novel transcriptional targets of the SRY-HMG box transcription factor SOX4 link its expression to the development of small cell lung cancer. , 2012, Cancer research.

[39]  Chin-Lee Wu,et al.  SOXs in human prostate cancer: implication as progression and prognosis factors , 2012, BMC Cancer.

[40]  D. Chan,et al.  SOX9 Governs Differentiation Stage-Specific Gene Expression in Growth Plate Chondrocytes via Direct Concomitant Transactivation and Repression , 2011, PLoS genetics.

[41]  R. Lovell-Badge,et al.  Reciprocal Repression between Sox3 and Snail Transcription Factors Defines Embryonic Territories at Gastrulation , 2011, Developmental cell.

[42]  E. Sverdlov,et al.  Heterogeneity and degree of TIMP4, GATA4, SOX18, and EGFL7 gene promoter methylation in non-small cell lung cancer and surrounding tissues. , 2011, Cancer genetics.

[43]  A. Knudson,et al.  A continuum model for tumour suppression , 2011, Nature.

[44]  M. Meyerson,et al.  SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer , 2011, Modern Pathology.

[45]  R. Xiang,et al.  Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer , 2011, British Journal of Cancer.

[46]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[47]  H. Okano,et al.  Expression and Function of Sox21 During Mouse Cochlea Development , 2011, Neurochemical Research.

[48]  Wei Yu,et al.  The SOX2 response program in glioblastoma multiforme: an integrated ChIP-seq, expression microarray, and microRNA analysis , 2011, BMC Genomics.

[49]  E. Lundberg,et al.  Towards a knowledge-based Human Protein Atlas , 2010, Nature Biotechnology.

[50]  J. Robertson,et al.  Autoimmunity to SOX2, clinical phenotype and survival in patients with small-cell lung cancer. , 2010, Lung cancer.

[51]  M. Toyoda,et al.  Defining Hypo-Methylated Regions of Stem Cell-Specific Promoters in Human iPS Cells Derived from Extra-Embryonic Amnions and Lung Fibroblasts , 2010, PloS one.

[52]  L. Chirieac,et al.  Sox2 Protein Expression is an Independent Poor Prognostic Indicator in Stage I Lung Adenocarcinoma , 2010, The American journal of surgical pathology.

[53]  C. Hsiung,et al.  Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity , 2010, Clinical Cancer Research.

[54]  Véronique Lefebvre,et al.  Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors , 2010, Nature communications.

[55]  S. Giannotti,et al.  Constitutive Expression of Pluripotency-Associated Genes in Mesodermal Progenitor Cells (MPCs) , 2010, PloS one.

[56]  M. Wegner All purpose Sox: The many roles of Sox proteins in gene expression. , 2010, The international journal of biochemistry & cell biology.

[57]  H. Kondoh,et al.  SOX-partner code for cell specification: Regulatory target selection and underlying molecular mechanisms. , 2010, The international journal of biochemistry & cell biology.

[58]  V. Harley,et al.  Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. , 2010, The international journal of biochemistry & cell biology.

[59]  A. Zorn,et al.  Interactions between SOX factors and Wnt/β‐catenin signaling in development and disease , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[60]  Z. Shao,et al.  Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer , 2010, Breast Cancer Research and Treatment.

[61]  Nicoletta Kessaris,et al.  SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch. , 2009, Biochemical and biophysical research communications.

[62]  A. Regev,et al.  SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas , 2009, Nature Genetics.

[63]  Jessica Mariani,et al.  Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh , 2009, Nature Neuroscience.

[64]  A. Twijnstra,et al.  SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Yingqun Wang,et al.  Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy , 2009, Molecular Cancer Therapeutics.

[66]  Ian Chambers,et al.  The transcriptional foundation of pluripotency , 2009, Development.

[67]  A. Blais,et al.  SOX15 and SOX7 Differentially Regulate the Myogenic Program in P19 Cells , 2009, Stem cells.

[68]  G. Pan,et al.  MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells , 2009, Cell.

[69]  J. Jessen Noncanonical Wnt signaling in tumor progression and metastasis. , 2009, Zebrafish.

[70]  V. Hearing,et al.  Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid. , 2009, The Journal of clinical investigation.

[71]  J. Cigudosa,et al.  The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. , 2009, Human molecular genetics.

[72]  Colleen D. McCabe,et al.  Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. , 2009, Cancer research.

[73]  Jing Liang,et al.  The Molecular Mechanism Governing the Oncogenic Potential of SOX2 in Breast Cancer* , 2008, Journal of Biological Chemistry.

[74]  P. Blache,et al.  Defective claudin-7 regulation by Tcf-4 and Sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cells. , 2008, Cancer research.

[75]  K. Yanagihara,et al.  SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis , 2008, British Journal of Cancer.

[76]  H. Aburatani,et al.  Overexpression of SOX15 inhibits proliferation of NT2/D1 cells derived from a testicular embryonal cell carcinoma. , 2007, Molecules and cells.

[77]  Wen-li Ma,et al.  Analysis of SOX4 gene mutation in non-small cell lung cancer tissues. , 2007, Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics.

[78]  Aaron M. Zorn,et al.  Sox17 and Sox4 Differentially Regulate β-Catenin/T-Cell Factor Activity and Proliferation of Colon Carcinoma Cells , 2007, Molecular and Cellular Biology.

[79]  R. Hammer,et al.  Sox15 and Fhl3 transcriptionally coactivate Foxk1 and regulate myogenic progenitor cells , 2007, The EMBO journal.

[80]  Tao Zhang,et al.  SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cells. , 2007, Cancer research.

[81]  Tao Zhang,et al.  SOX 9 Is Expressed in Normal Prostate Basal Cells and Regulates Androgen Receptor Expression in Prostate Cancer Cells , 2007 .

[82]  V. Harley,et al.  SOX13 Exhibits a Distinct Spatial and Temporal Expression Pattern During Chondrogenesis, Neurogenesis, and Limb Development , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[83]  Pengbo Liu,et al.  Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. , 2006, Cancer research.

[84]  Shinya Yamanaka,et al.  Differential Roles for Sox15 and Sox2 in Transcriptional Control in Mouse Embryonic Stem Cells* , 2005, Journal of Biological Chemistry.

[85]  M. Ochs,et al.  Sox15 Is Required for Skeletal Muscle Regeneration , 2004, Molecular and Cellular Biology.

[86]  D. Wilhelm,et al.  Sox genes and cancer , 2004, Cytogenetic and Genome Research.

[87]  Li-Ru Zhao,et al.  Sox1 acts through multiple independent pathways to promote neurogenesis. , 2004, Developmental biology.

[88]  J. Bowles,et al.  Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. , 2000, Developmental biology.

[89]  P. Berta,et al.  Muscle Differentiation Is Antagonized by SOX15, a New Member of the SOX Protein Family* , 2000, The Journal of Biological Chemistry.

[90]  H. Kondoh,et al.  Pairing SOX off: with partners in the regulation of embryonic development. , 2000, Trends in genetics : TIG.

[91]  P. Goodfellow,et al.  cDNA characterization and high resolution mapping of the human SOX20 gene , 1998, Mammalian Genome.

[92]  Véronique Lefebvre,et al.  A new long form of Sox5 (L‐Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene , 1998, The EMBO journal.

[93]  Peter Goodfellow,et al.  A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes , 1990, Nature.