title: PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer.
abstract: Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy.
authors.affiliation: Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Lee
authors.affiliation: 1] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Sung
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: W H
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-W
authors.initials: HW
authors.lastname: Shin
authors.affiliation: 1] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: C-H
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Li
authors.affiliation: 1] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-D
authors.initials: HD
authors.lastname: Youn
authors.affiliation: 1] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea [3] Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: 1] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea [3] Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chun
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D057809:HEK293 Cells; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018398:Homeodomain Proteins; C117905:PHF2 protein, human; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53