title: Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
abstract: The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Shuai
authors.initials: S
authors.lastname: Ma
authors.forename: Nan
authors.initials: N
authors.lastname: Song
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Shangda
authors.initials: S
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Ding
authors.forename: Lin
authors.initials: L
authors.lastname: Shan
authors.forename: Xing
authors.initials: X
authors.lastname: Zhou
authors.forename: Dongxue
authors.initials: D
authors.lastname: Su
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Yu
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D063646:Carcinogenesis; D056751:Cyclin A2 / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004795:Enzyme Stability; D044127:Epigenesis, Genetic; D005260:Female; D056466:Histone Demethylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D015854:Up-Regulation
chemical_list: C503721:CCNA2 protein, human; D056751:Cyclin A2; D034741:RNA, Small Interfering; D014157:Transcription Factors; D056466:Histone Demethylases; C511934:PHF8 protein, human; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7