title: Double mutant P53 (N340Q/L344R) promotes hepatocarcinogenesis through upregulation of Pim1 mediated by PKM2 and LncRNA CUDR.
abstract: P53 is frequently mutated in human tumors as a novel gain-of-function to promote tumor development. Although dimeric (M340Q/L344R) influences on tetramerisation on site-specific post-translational modifications of p53, it is not clear how dimeric (M340Q/L344R) plays a role during hepatocarcinogenesis. Herein, we reveal that P53 (N340Q/L344R) promotes hepatocarcinogenesis through upregulation of PKM2. Mechanistically, P53 (N340Q/L344R) forms complex with CUDR and the complex binds to the promoter regions of PKM2 which enhances the expression, phosphorylation of PKM2 and its polymer formation. Thereby, the polymer PKM2 (tetramer) binds to the eleventh threonine on histone H3 that increases the phosphorylation of the eleventh threonine on histone H3 (pH3T11). Furthermore, pH3T11 blocks HDAC3 binding to H3K9Ac that prevents H3K9Ac from deacetylation and stabilizes the H3K9Ac modification. On the other hand, it also decreased tri-methylation of histone H3 on the ninth lysine (H3K9me3) and increases one methylation of histone H3 on the ninth lysine (H3K9me1). Moreover, the combination of H3K9me1 and HP1 α forms more H3K9me3-HP1α complex which binds to the promoter region of Pim1, enhancing the expression of Pim1 that enhances the expression of TERT, oncogenic lncRNA HOTAIR and reduces the TERRA expression. Ultimately, P53 (N340Q/L344R) accerlerates the growth of liver cancer cells Hep3B by activating telomerase and prolonging telomere through the cascade of P53 (N340Q/L344R)-CUDR-PKM2-pH3T11- (H3K9me1-HP1α)-Pim1- (TERT-HOTAIR-TERRA). Understanding the novel functions of P53 (N340Q/L344R) will help in the development of new liver cancer therapeutic approaches that may be useful in a broad range of cancer types.
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Wu
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: An
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Xiaoru
authors.initials: X
authors.lastname: Xin
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Zhuojia
authors.initials: Z
authors.lastname: Lin
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Lu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D000090266:Chromobox Protein Homolog 5; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis* / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics*; D013963:Thyroid Hormones / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D000090266:Chromobox Protein Homolog 5; D008565:Membrane Proteins; D051573:Proto-Oncogene Proteins c-pim-1; D062085:RNA, Long Noncoding; D013963:Thyroid Hormones; D016159:Tumor Suppressor Protein p53; D000097810:Thyroid Hormone-Binding Proteins; C000715594:CBX5 protein, human; C495901:TP53 protein, human; C515159:UCA1 RNA, human; C496634:PIM1 protein, human
keywords: LncRNA CUDR; PKM2; hepatoma; mutant P53 (N340Q/L344R)