title: Epigenetic regulation of REG1A and chemosensitivity of cutaneous melanoma.
abstract: Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in epithelium origin tumors; however, its role in melanoma has not been explored in details. The objective of this study was to identify whether REG1A is expressed in cutaneous melanoma and if REG1A expression status can predict prognosis in cutaneous melanoma patients with metastasis. We also determined whether epigenetic regulation of the promoter region regulates REG1A expression. AJCC stage III cutaneous melanoma specimens with clinically well annotated stage III lymph node melanoma metastasis tissue microarray were assessed by IHC. MALDI-TOF-mass spectrometry and HM450K array were used to identify REG1A promoter region CpG site methylation. Chemotherapeutic agent response by melanoma cells as related to REG1A protein expression was assessed. Post-surgery melanoma patients followed by adjuvant chemotherapy with high REG1A expression had a significantly better prognosis (disease-specific survival) compared with patients with low REG1A expression (log rank test; p = 0.0013). The demethylating reagent 5-Aza-2'-deoxycytidine activated REG1A promoter region resulting in enhanced REG1A mRNA and protein expression in melanoma cell lines. Promoter region CpG methylation was shown to regulate REG1A expression in melanoma cells. Moreover, melanoma lines with high REG1A mRNA expression were more susceptible to Dacarbazine and Cisplatin, as compared with those with low REG1A mRNA expression. In conclusion, REG1A expression status may be useful as a biomarker in melanoma patients for sensitivity to these chemotherapeutic agents. The epigenetic regulation of the REG1A promoter region may offer a potential therapeutic approach to improve chemotherapy for metastatic melanoma patients.
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Marzese
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Division of Biostatistics; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Myung Shin
authors.initials: MS
authors.lastname: Sim
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chong
authors.affiliation: Department of Molecular Oncology; John Wayne Cancer Institute; Santa Monica, CA USA.
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019175:DNA Methylation; D003606:Dacarbazine / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006801:Humans; D051847:Lithostathine / Q000235:genetics*; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051847:Lithostathine; C497617:REG1A protein, human; D003606:Dacarbazine; D002945:Cisplatin
keywords: REG1A; chemosensitivity; melanoma; metastasis; methylation
references.citation: CMAJ. 2006 Jan 31;174(3):341-8
references.pmid: 16446478
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Epigenetics. 2011 Aug;6(8):1001-11
references.pmid: 21725199
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2331s-2336s
references.pmid: 16609054
references.citation: Epigenetics. 2011 Mar;6(3):388-94
references.pmid: 21081840
references.citation: FEBS Lett. 2006 Jan 23;580(2):585-91
references.pmid: 16405968
references.citation: Cancer. 2010 Jun 15;116(12):2868-77
references.pmid: 20564393
references.citation: Ann Surg Oncol. 2006 Dec;13(12):1724-31
references.pmid: 17009160
references.citation: Oncogene. 2006 Jan 26;25(4):599-608
references.pmid: 16314847
references.citation: J Biol Chem. 1988 Feb 15;263(5):2111-4
references.pmid: 2963000
references.citation: J Surg Res. 2008 Jan;144(1):29-35
references.pmid: 17950328
references.citation: Clin Chem. 2009 Apr;55(4):611-22
references.pmid: 19246619
references.citation: N Engl J Med. 2010 Aug 26;363(9):809-19
references.pmid: 20818844
references.citation: J Biol Chem. 1990 May 5;265(13):7432-9
references.pmid: 2332435
references.citation: Oncogene. 2004 Apr 29;23(20):3572-9
references.pmid: 15116092
references.citation: N Engl J Med. 2006 Sep 28;355(13):1307-17
references.pmid: 17005948
references.citation: Clin Cancer Res. 2009 May 1;15(9):2988-94
references.pmid: 19336521
references.citation: Ann Surg Oncol. 2008 Apr;15(4):1224-31
references.pmid: 18259819
references.citation: Am J Gastroenterol. 2005 Oct;100(10):2157-66
references.pmid: 16181363
references.citation: Cancer. 1992 Oct 1;70(7):1857-63
references.pmid: 1525759
references.citation: Ann Surg Oncol. 2008 Nov;15(11):3244-51
references.pmid: 18781363
references.citation: Oncogene. 2004 May 13;23(22):4014-22
references.pmid: 15064737
references.citation: Clin Cancer Res. 2000 Dec;6(12):4859-65
references.pmid: 11156245
references.citation: Eur J Surg Oncol. 2009 Aug;35(8):852-7
references.pmid: 19167858
references.citation: Adv Exp Med Biol. 1992;321:61-6; discussion 67-9
references.pmid: 1449083
references.citation: Nucleic Acids Res. 2013 Apr;41(7):e90
references.pmid: 23476028
references.citation: Eur J Cancer. 2005 Aug;41(12):1690-6
references.pmid: 16043346
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1801-7
references.pmid: 19223509
references.citation: Cancer Lett. 2014 Jan 28;342(2):170-7
references.pmid: 22289720
references.citation: Int J Cancer. 2008 Jul 15;123(2):409-413
references.pmid: 18452172
references.citation: Am J Pathol. 2012 Jul;181(1):257-67
references.pmid: 22626806
references.citation: Lung Cancer. 2008 Apr;60(1):98-104
references.pmid: 17964685
references.citation: Oncogene. 2009 Aug 27;28(34):3058-68
references.pmid: 19561646
references.citation: Oncogene. 2012 Apr 12;31(15):1869-83
references.pmid: 21892204
references.citation: J Natl Cancer Inst. 2010 Apr 7;102(7):493-501
references.pmid: 20179267
references.citation: Ann Surg Oncol. 2013 Sep;20(9):3044-51
references.pmid: 23645481
references.citation: Carcinogenesis. 2008 Jan;29(1):76-83
references.pmid: 18024479