DNA methylation and microRNA dysregulation in cancer

DNA methylation plays a key role in the silencing of numerous cancer‐related genes, thereby affecting a number of vital cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion and angiogenesis. Also widely altered in human malignancies is the expression of microRNAs (miRNAs), a class of small noncoding RNAs that act as posttranscriptional regulators of gene expression. Furthermore, emerging evidence now supports the idea that DNA methylation is crucially involved in the dysregulation of miRNAs in cancer. This is in part the result of technological advances that enable more comprehensive analysis of miRNA expression profiles and the epigenome in cancer cells, which has led to the identification of a number of epigenetically regulated miRNAs. As with protein‐coding genes, it appears that miRNA genes involved in regulating cancer‐related pathways are silenced in association with CpG island hypermethylation. In addition, methylation in CpG island shore regions and DNA hypomethylation also appear to contribute to miRNA dysregulation in cancer. Aberrant DNA methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Moreover, re‐expression of miRNAs and the replacement of tumor suppressive miRNAs using miRNA mimics or expression vectors could be effective approaches to cancer therapy.

[1]  Peter A. Jones,et al.  Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. , 2006, Cancer cell.

[2]  A. Hui,et al.  Significance of Dysregulated Metadherin and MicroRNA-375 in Head and Neck Cancer , 2011, Clinical Cancer Research.

[3]  P. Jin,et al.  MicroRNA miR‐137 Regulates Neuronal Maturation by Targeting Ubiquitin Ligase Mind Bomb‐1 , 2010, Stem cells.

[4]  M. Toyota,et al.  Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. , 2010, Carcinogenesis.

[5]  Shaojie Zhang,et al.  Epigenetic regulation of microRNA‐375 and its role in melanoma development in humans , 2011, FEBS letters.

[6]  C. Croce,et al.  Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells. , 2010, Cancer research.

[7]  Jørgen Kjems,et al.  Coordinated epigenetic repression of the miR‐200 family and miR‐205 in invasive bladder cancer , 2011, International journal of cancer.

[8]  Jingqin Luo,et al.  Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. , 2009, Cancer research.

[9]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Carola Berking,et al.  Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer , 2008, Cell cycle.

[11]  C. Boland,et al.  Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis. , 2010, Cancer research.

[12]  M. Toyota,et al.  Genome-wide profiling of chromatin signatures reveals epigenetic regulation of MicroRNA genes in colorectal cancer. , 2011, Cancer research.

[13]  K. Kelnar,et al.  Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. , 2010, Cancer research.

[14]  M. Tatematsu,et al.  DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: Its possible involvement in the formation of epigenetic field defect , 2009, International journal of cancer.

[15]  K. Kelnar,et al.  The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. , 2011, Nature medicine.

[16]  R. Siebert,et al.  Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. , 2009, Cancer research.

[17]  Thomas D. Schmittgen,et al.  Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. , 2008, Cancer research.

[18]  D. Takai,et al.  CpG island methylation of microRNAs is associated with tumor size and recurrence of non‐small‐cell lung cancer , 2011, Cancer science.

[19]  R. Dahiya,et al.  The functional significance of microRNA-145 in prostate cancer , 2010, British Journal of Cancer.

[20]  H. Lodish,et al.  Distinct roles for miR‐1 and miR‐133a in the proliferation and differentiation of rhabdomyosarcoma cells , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  Wenlin Huang,et al.  miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. , 2011, Cancer research.

[22]  C. Croce.  Causes and consequences of microRNA dysregulation in cancer , 2009, Nature Reviews Genetics.

[23]  H. Sültmann,et al.  The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. , 2007, Cancer research.

[24]  T. Hibi,et al.  Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells , 2009, Oncogene.

[25]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[26]  J. Gu,et al.  Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma , 2010, Oncogene.

[27]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[28]  X. Chen,et al.  miR‐137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells , 2011, International journal of cancer.

[29]  C. Morrison,et al.  MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B , 2007, Proceedings of the National Academy of Sciences.

[30]  J. Costello,et al.  Epigenetic silencing of MIR203 in multiple myeloma , 2011, British journal of haematology.

[31]  Zhaoli Chen,et al.  DNA hypermethylation of microRNA-34b/c has prognostic value for stage Ⅰ non-small cell lung cancer , 2011, Cancer biology & therapy.

[32]  M. Korpal,et al.  The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2* , 2008, Journal of Biological Chemistry.

[33]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[34]  Y. Nakajima,et al.  Annexin II overexpression correlates with stromal tenascin‐C overexpression , 2001, Cancer.

[35]  Min Zhang,et al.  MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells , 2009, PloS one.

[36]  Tasneem Motiwala,et al.  Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer , 2008, Journal of Biological Chemistry.

[37]  Y. Yuasa,et al.  MiR‐9 downregulates CDX2 expression in gastric cancer cells , 2011, International journal of cancer.

[38]  N. Seki,et al.  Restoration of miR-145 expression suppresses cell proliferation, migration and invasion in prostate cancer by targeting FSCN1. , 2011, International journal of oncology.

[39]  S. Ropero,et al.  A microRNA DNA methylation signature for human cancer metastasis , 2008, Proceedings of the National Academy of Sciences.

[40]  H. Allgayer,et al.  Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer , 2010, Molecular Cancer Research.

[41]  M. Toyota,et al.  Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors , 2011, Cancer Prevention Research.

[42]  Shu Shimada,et al.  Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. , 2010, Carcinogenesis.

[43]  J. Soh,et al.  Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma , 2011, Clinical Cancer Research.

[44]  V. Díaz,et al.  Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro , 2004, Gut.

[45]  Xabier Agirre,et al.  Epigenetic regulation of microRNA expression in colorectal cancer , 2009, International journal of cancer.

[46]  M. Esteller,et al.  Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis , 2011, Oncogene.

[47]  A. Choi,et al.  Identification and Functional Analysis of Epigenetically Silenced MicroRNAs in Colorectal Cancer Cells , 2011, PloS one.

[48]  H. Trompeter,et al.  Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells , 2010, BMC Research Notes.

[49]  Scott M Langevin,et al.  MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. , 2010, Carcinogenesis.

[50]  Martha R. Stampfer,et al.  Role for DNA Methylation in the Regulation of miR-200c and miR-141 Expression in Normal and Cancer Cells , 2010, PloS one.

[51]  Sun-Mi Park,et al.  The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. , 2008, Genes & development.

[52]  Sung-Chou Li,et al.  Epigenetic regulation of miR‐196b expression in gastric cancer , 2010, Genes, chromosomes & cancer.

[53]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[54]  U. Lehmann,et al.  Epigenetic inactivation of microRNA gene hsa‐mir‐9‐1 in human breast cancer , 2008, The Journal of pathology.

[55]  Yan Wang,et al.  CpG island methylation status of miRNAs in esophageal squamous cell carcinoma , 2012, International journal of cancer.

[56]  M. Gariboldi,et al.  miRNA Profiling in Colorectal Cancer Highlights miR-1 Involvement in MET-Dependent Proliferation , 2012, Molecular Cancer Research.

[57]  S. Kakar,et al.  MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. , 2011, Carcinogenesis.

[58]  Hui Wang,et al.  MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. , 2011, Carcinogenesis.

[59]  R. Agami,et al.  Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer , 2010, Molecular Cancer.

[60]  R. Siebert,et al.  Epigenetic regulation of microRNAs in acute lymphoblastic leukemia. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  M. Seto,et al.  MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. , 2010, Cancer research.

[62]  F. Hamdy,et al.  Hypermethylation of CpG Islands and Shores around Specific MicroRNAs and Mirtrons Is Associated with the Phenotype and Presence of Bladder Cancer , 2010, Clinical Cancer Research.

[63]  L. Gao,et al.  MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia , 2011, Oncogene.

[64]  Jun Yu,et al.  MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer , 2009, British Journal of Cancer.

[65]  Q. Fan,et al.  miR-137 Is Frequently Down-Regulated in Gastric Cancer and Is a Negative Regulator of Cdc42 , 2011, Digestive Diseases and Sciences.

[66]  M. Toyota,et al.  DNA methylation and cancer pathways in gastrointestinal tumors. , 2008, Pharmacogenomics.

[67]  J. Rowley,et al.  Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. , 2009, Blood.

[68]  L. Buscail,et al.  The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. , 2010, Clinical chemistry.

[69]  F. Yu,et al.  MicroRNA 34c Gene Down-regulation via DNA Methylation Promotes Self-renewal and Epithelial-Mesenchymal Transition in Breast Tumor-initiating Cells* , 2011, The Journal of Biological Chemistry.

[70]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[71]  S. Leng,et al.  EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. , 2011, Cancer research.

[72]  Kimberly Walter,et al.  Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. , 2010, Cancer research.

[73]  Jun S. Song,et al.  Chromatin structure analyses identify miRNA promoters , 2008 .

[74]  J. Inazawa,et al.  The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. , 2011, Cancer research.

[75]  M. Esteller,et al.  DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer , 2011, Oncogene.

[76]  B. Verdoodt,et al.  Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas , 2011, Virchows Archiv.

[77]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[78]  P. Jin,et al.  Cross talk between microRNA and epigenetic regulation in adult neurogenesis , 2010, The Journal of cell biology.

[79]  J. Inazawa,et al.  Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. , 2008, Cancer research.

[80]  Yi Qu,et al.  Genome-Wide Profiling of Histone H3 Lysine 4 and Lysine 27 Trimethylation Reveals an Epigenetic Signature in Prostate Carcinogenesis , 2009, PloS one.

[81]  M. Esteller.  Non-coding RNAs in human disease , 2011, Nature Reviews Genetics.

[82]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[83]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[84]  Kelong Ma,et al.  Hypomethylation of the hsa-miR-191 locus causes high expression of hsa-mir-191 and promotes the epithelial-to-mesenchymal transition in hepatocellular carcinoma. , 2011, Neoplasia.

[85]  R. Stone,et al.  MicroRNA‐137 promoter methylation is associated with poorer overall survival in patients with squamous cell carcinoma of the head and neck , 2011, Cancer.

[86]  Xiaoling Lin,et al.  Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. , 2010, Biochemical and biophysical research communications.

[87]  F. Prósper,et al.  Deregulation of FGFR1 and CDK6 oncogenic pathways in acute lymphoblastic leukaemia harbouring epigenetic modifications of the MIR9 family , 2011, British journal of haematology.

[88]  T. Rohan,et al.  Hsa‐miR‐375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity , 2012, The Journal of pathology.

[89]  J. Inazawa,et al.  miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. , 2011, Cancer research.

[90]  Hubert Rehrauer,et al.  Epigenetic silencing of microRNA-203 dysregulates ABL1 expression and drives Helicobacter-associated gastric lymphomagenesis. , 2011, Cancer research.

[91]  Shinji Tanaka,et al.  miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. , 2010, Carcinogenesis.

[92]  Jingde Zhu,et al.  DNA Methylation-regulated miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression* , 2011, The Journal of Biological Chemistry.

[93]  A. Jimeno,et al.  Genome-wide profiling at methylated promoters in pancreatic adenocarcinoma , 2008, Cancer biology & therapy.

[94]  Brian S. Roberts,et al.  The colorectal microRNAome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Jiansheng Li,et al.  Epigenetic Silencing of MicroRNA-375 Regulates PDK1 Expression in Esophageal Cancer , 2011, Digestive Diseases and Sciences.

[96]  Sandya Liyanarachchi,et al.  Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. , 2009, Cancer research.

[97]  F. Roviello,et al.  Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer , 2011, British Journal of Cancer.

[98]  Wen-Ching Chan,et al.  Aberrant hypermethylation of miR-9 genes in gastric cancer , 2011, Epigenetics.

[99]  K. Kelnar,et al.  The microRNA miR-34 a inhibits prostate cancer stem cells and metastasis by directly repressing CD 44 , 2010 .

[100]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[101]  Renato Baserga,et al.  Micro RNA 145 Targets the Insulin Receptor Substrate-1 and Inhibits the Growth of Colon Cancer Cells* , 2007, Journal of Biological Chemistry.

[102]  C. Croce,et al.  MicroRNA signatures in human ovarian cancer. , 2007, Cancer research.

[103]  R. Hartmann,et al.  MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. , 2011, Cancer research.

[104]  D. Khaitan,et al.  Epigenetic Regulation of MicroRNA Genes and the Role of miR-34b in Cell Invasion and Motility in Human Melanoma , 2011, PloS one.

[105]  Sung-Chou Li,et al.  Epigenetic regulation of miR‐34b and miR‐129 expression in gastric cancer , 2011, International journal of cancer.

[106]  M. Toyota,et al.  Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. , 2008, Cancer research.

[107]  D. Takai,et al.  Genome structure‐based screening identified epigenetically silenced microRNA associated with invasiveness in non‐small‐cell lung cancer , 2012, International journal of cancer.

[108]  Ying Feng,et al.  Supplemental Data P53-mediated Activation of Mirna34 Candidate Tumor-suppressor Genes , 2022 .

[109]  J. Cigudosa,et al.  Genetic and Epigenetic Silencing of microRNA-203 Enhances ABL 1 and BCR-ABL 1 Oncogene Expression , 2008 .

[110]  D. Peeper,et al.  Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB , 2004, Nature.

[111]  S. Law,et al.  MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor , 2011, Gut.

[112]  Thomas D. Schmittgen,et al.  microRNA Replacement Therapy for Cancer , 2011, Pharmaceutical Research.

[113]  Hailin Tang,et al.  MiR-185 Targets the DNA Methyltransferases 1 and Regulates Global DNA Methylation in human glioma , 2011, Molecular Cancer.

[114]  Yue Wang,et al.  Down‐regulated microRNA‐152 induces aberrant DNA methylation in hepatitis B virus–related hepatocellular carcinoma by targeting DNA methyltransferase 1 , 2010, Hepatology.

[115]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[116]  Y. Mo,et al.  MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. , 2010, Cancer research.

[117]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[118]  L. Cope,et al.  A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells. , 2008, Cancer research.

[119]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[120]  Kwan Yeung Wong,et al.  Epigenetic Inactivation of the miR-124-1 in Haematological Malignancies , 2010, PloS one.

[121]  M. Fraga,et al.  Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. , 2007, Cancer research.

[122]  T. Patel,et al.  MicroRNA‐dependent regulation of DNA methyltransferase‐1 and tumor suppressor gene expression by interleukin‐6 in human malignant cholangiocytes , 2010, Hepatology.