title: Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway.
abstract: Menin, the product of the Men1 gene, which is frequently mutated in pancreatic neuroendocrine tumors, acts as a chromatin-remodeling factor to modulate the transcription of cell cycle regulators by interacting with histone modification factors. However, the function of menin and its underlying mechanisms in pancreatic ductal adenocarcinoma remain unknown. Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis. Menin overexpression significantly activated the expression of the cyclin-dependent kinase (CDK) inhibitors p18 and p27, accompanied with a decrease in DNA methylation levels of p18 and p27 promoters. Mechanistically, we found that interaction of menin with DNA methyltransferase 1 (Dnmt1) competitively pulled down Dnmt1 from p18 and p27 promoters, leading to the downregulation of DNA methylation levels. Moreover, menin expression was suppressed by Dnmt1 downstream of the Hedgehog signaling pathway, and menin overexpression strongly antagonized the promotion effect of hedgehog signaling on pancreatic cancer cell proliferation. Taken together, the interaction between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of Hedgehog pathways with complex mutual modulation networks, suggesting that the Hedgehog/Dnmt1/menin axis is a potential molecular target for pancreatic cancer therapy.
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Sheng-sheng
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Che
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: jingangjg@126.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xian-Gui
authors.initials: XG
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D003514:Cyclohexylamines / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D019175:DNA Methylation; D005260:Female; D053823:Hedgehog Proteins / Q000819:agonists / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C493971:CDKN2C protein, human; D050763:Cyclin-Dependent Kinase Inhibitor p18; D003514:Cyclohexylamines; D053823:Hedgehog Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; C468918:SAG compound; D013876:Thiophenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
keywords: Dnmt1; Menin; Methylation; Pancreatic cancer cell growth; p18; p27