title: MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B.
abstract: The histone variant, macroH2A1, has an important role in embryonic stem cell differentiation and tumor progression in various types of tumors. However, the regulatory roles of macroH2A1 on bladder cancer progression have not been fully elucidated. Here, we show that macroH2A1 knockdown promotes stem-like properties of bladder cancer cells. The knockdown of macroH2A1 in bladder cancer cells increased tumorigenicity, radioresistance, degeneration of reactive oxygen species, increased sphere formation capability and an increase in the proportion of side populations. We found that macroH2A1 is required for the suppression of Lin28B identified as a novel downstream target of macroH2A1 in bladder cancer. Loss of macroH2A1 expression significantly correlated with the elevated levels of Lin28B expression and subsequently inhibited the mature let-7 microRNA expression. Furthermore, the stable overexpression of Lin28B enhances the several phenotypes, including tumorigenicity and sphere-forming ability, which are induced by macroH2A1 depletion. Importantly, Lin28B expression was regulated by macroH2A1-mediated reciprocal binding of p300 and EZH2/SUV39H1. Our results suggest that Lin28B/let-7 pathway is tightly regulated by macroH2A1 and its cofactors, and have a pivotal role in the bladder tumor progression and the regulation of stem-like characteristics of bladder cancer cells.
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.|Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Shim
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: D-Y
authors.initials: DY
authors.lastname: Eum
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: M-T
authors.initials: MT
authors.lastname: Park
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Mi Yi
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: S D
authors.initials: SD
authors.lastname: Kim
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: T G
authors.initials: TG
authors.lastname: Son
authors.affiliation: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: N D
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.|Department of Radiation Oncology, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea.|Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: K
authors.initials: K
authors.lastname: Yang
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan, Republic of Korea.
authors.forename: K
authors.initials: K
authors.lastname: Heo
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D015533:Transcriptional Activation; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D006657:Histones; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human