SATB2 suppresses the progression of colorectal cancer cells via inactivation of MEK5/ERK5 signaling

Special AT‐rich sequence binding protein 2 (SATB2) is an evolutionarily conserved transcription factor that has multiple roles in neuronal development, osteoblast differentiation, and craniofacial patterning. SATB2 binds to the nuclear matrix attachment region, and regulates the expression of diverse sets of genes by altering chromatin structure. Recent studies have reported that high expression of SATB2 is associated with favorable prognosis in colorectal and laryngeal cancer; however, it remains uncertain whether SATB2 has tumor‐suppressive functions in cancer cells. In this study, we examined the effects of SATB2 expression on the malignant characteristics of colorectal cancer cells. Expression of SATB2 repressed the proliferation of cancer cells in vitro and in vivo, and also suppressed their migration and invasion. Extracellular signal‐regulated kinase 5 (ERK5) is a mitogen‐activated protein kinase that is associated with an aggressive phenotype in various types of cancer. SATB2 expression reduced the activity of ERK5, and constitutive activation of ERK5 restored the proliferation, anchorage‐independent growth, migration and invasion of SATB2‐expressing cells. Our results demonstrate the existence of a novel regulatory mechanism of SATB2‐mediated tumor suppression via ERK5 inactivation.

[1]  O. Britanova,et al.  Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development. , 2006, American journal of human genetics.

[2]  C. Marshall,et al.  Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton , 2005, Journal of Cell Science.

[3]  J. Yanagisawa,et al.  A matrix attachment region (MAR)-binding activity due to a p114 kilodalton protein is found only in human breast carcinomas and not in normal and benign breast disease tissues. , 1996, Cancer research.

[4]  O. Britanova,et al.  Satb2 Is a Postmitotic Determinant for Upper-Layer Neuron Specification in the Neocortex , 2008, Neuron.

[5]  D. Neal,et al.  MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion , 2003, Oncogene.

[6]  Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer , 2012, BMC Cancer.

[7]  T. Beaty,et al.  Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations , 2006, Human Genetics.

[8]  J. Chen,et al.  MicroRNA expression signature for Satb2-induced osteogenic differentiation in bone marrow stromal cells , 2013, Molecular and Cellular Biochemistry.

[9]  Y. Kohwi,et al.  Genome organizing function of SATB1 in tumor progression. , 2013, Seminars in cancer biology.

[10]  T. Jenuwein,et al.  Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression. , 2009, Genes & development.

[11]  O. Britanova,et al.  Novel transcription factor Satb2 interacts with matrix attachment region DNA elements in a tissue‐specific manner and demonstrates cell‐type‐dependent expression in the developing mouse CNS , 2005, The European journal of neuroscience.

[12]  V. Tarabykin,et al.  SATB2 interacts with chromatin‐remodeling molecules in differentiating cortical neurons , 2008, The European journal of neuroscience.

[13]  S. Cook,et al.  ERK5 and its role in tumour development. , 2012, Biochemical Society transactions.

[14]  Saraswati Sukumar,et al.  The Hox genes and their roles in oncogenesis , 2010, Nature Reviews Cancer.

[15]  X. Lu,et al.  Expression of SATB1 and heparanase in gastric cancer and its relationship to clinicopathologic features , 2010, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[16]  J. Rosenfeld,et al.  Small Deletions of SATB2 Cause Some of the Clinical Features of the 2q33.1 Microdeletion Syndrome , 2009, PloS one.

[17]  A. Aigner,et al.  Multiple effects of the special AT‐rich binding protein 1 (SATB1) in colon carcinoma , 2014, International journal of cancer.

[18]  M. Schubach,et al.  Further delineation of the SATB2 phenotype , 2013, European Journal of Human Genetics.

[19]  H. Uchi,et al.  Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanoma. , 2011, Journal of dermatological science.

[20]  Andre J. van Wijnen,et al.  A network connecting Runx2, SATB2, and the miR-23a∼27a∼24-2 cluster regulates the osteoblast differentiation program , 2010, Proceedings of the National Academy of Sciences.

[21]  J. Hardcastle,et al.  Colorectal cancer , 1993, Europe Against Cancer European Commission Series for General Practitioners.

[22]  S. Mcconnell,et al.  Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex , 2008, Neuron.

[23]  Tayard Desudchit,et al.  Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects , 2007, Human mutation.

[24]  M. Uhlén,et al.  A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer , 2012, British Journal of Cancer.

[25]  I. Fariñas,et al.  SATB2 Is a Multifunctional Determinant of Craniofacial Patterning and Osteoblast Differentiation , 2006, Cell.

[26]  J. Rosenfeld,et al.  Case series: 2q33.1 microdeletion syndrome—further delineation of the phenotype , 2011, Journal of Medical Genetics.

[27]  Q. Tong,et al.  SATB1 is an independent prognostic marker for gastric cancer in a Chinese population. , 2010, Oncology reports.

[28]  M. Zeng,et al.  Decreased Expression of SATB2: A Novel Independent Prognostic Marker of Worse Outcome in Laryngeal Carcinoma Patients , 2012, PloS one.

[29]  B. Nordlinger,et al.  Colorectal cancer – Authors' reply , 2010, The Lancet.

[30]  Jurgen Müller,et al.  ERK5: structure, regulation and function. , 2012, Cellular signalling.

[31]  I. Mian,et al.  SATB1 Cleavage by Caspase 6 Disrupts PDZ Domain-Mediated Dimerization, Causing Detachment from Chromatin Early in T-Cell Apoptosis , 2001, Molecular and Cellular Biology.

[32]  J. Russo,et al.  SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis , 2008, Nature.

[33]  D. Bonthron,et al.  Identification of SATB2 as the cleft palate gene on 2q32-q33. , 2003, Human molecular genetics.

[34]  Jian-ming Li,et al.  Down‐regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer , 2009, The Journal of pathology.

[35]  R. Grosschedl,et al.  SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression. , 2003, Genes & development.

[36]  Shuang Wang,et al.  Elevated MicroRNA-31 Expression Regulates Colorectal Cancer Progression by Repressing Its Target Gene SATB2 , 2013, PloS one.