Luo Yanwei, Wang Xinye, Niu Weihong, Zhou Yao, Li Mengna, Ma Jinqi, Yang Jing, Fan Songqing, Zeng Zhaoyang, Xiong Wei, Li Xiaoling, Li Guiyuan, Xiao Jidong, Zhou Ming
NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China.
J Cancer. 2022 Feb 28;13(5):1436-1448. doi: 10.7150/jca.67447. eCollection 2022.
Bromodomain-containing protein 7 (BRD7) was found to be down-expressed in nasopharyngeal carcinoma as well as breast cancer and to function as a potential tumor suppressor. BRD7 interacts with p53 and is required for p53-dependent oncogene-induced senescence. However, the mechanism how BRD7 functions as tumor suppressor roles in breast cancer remains unclear. MTT, colony formation assay, cell cycle, cell apoptosis, and tumorigenicity assays were performed to evaluate the biological functions of BRD7 in breast cancer cells . Real-time PCR, western blot, luciferase reporter gene assays, and co-immunoprecipitation were used to examine the gene expression, transcription activation and protein-protein interaction. We reported that BRD7 effectively suppressed cell proliferation and tumor growth and . In addition, BRD7 increased p53 protein stability through ubiquitin-dependent proteasome pathway and regulated the expression of p53 downstream target genes by activating its transcriptional activity in breast cancers harboring wild-type p53. Mechanistically, BRD7 decreased phosphorylation and activation of MDM2 via inactivating its upstream kinase AKT depending on the bromodomain of BRD7, therefore BRD7 significantly reduced the amounts of phosphorylated MDM2 binding with p53 eventually decreasing ubiquitination level of p53. Furthermore, silencing the expression of p53 at least partly reversed the inhibition effect of BRD7 on cell proliferation and tumor growth and . Our studies identify that BRD7 stabilizes p53 by inhibiting the phosphorylation of MDM2 via AKT pathway dependent on its bromodomain to function as a tumor suppressor in breast cancer harboring wild-type p53.
含溴结构域蛋白7（BRD7）在鼻咽癌以及乳腺癌中呈低表达，具有潜在的肿瘤抑制功能。BRD7与p53相互作用，是p53依赖的癌基因诱导衰老所必需的。然而，BRD7在乳腺癌中发挥肿瘤抑制作用的机制仍不清楚。通过MTT、集落形成实验、细胞周期、细胞凋亡和致瘤性实验来评估BRD7在乳腺癌细胞中的生物学功能。采用实时荧光定量PCR、蛋白质免疫印迹法、荧光素酶报告基因实验和免疫共沉淀法检测基因表达、转录激活及蛋白质-蛋白质相互作用。我们报道BRD7能有效抑制细胞增殖和肿瘤生长。此外，在携带野生型p53的乳腺癌中，BRD7通过泛素依赖的蛋白酶体途径增加p53蛋白稳定性，并通过激活其转录活性来调控p53下游靶基因的表达。机制上，BRD7通过使其上游激酶AKT失活，依赖其溴结构域降低MDM2的磷酸化和激活，因此BRD7显著减少与p53结合的磷酸化MDM2的量，最终降低p53的泛素化水平。此外，沉默p53的表达至少部分逆转了BRD7对细胞增殖和肿瘤生长的抑制作用。我们的研究表明，在携带野生型p53的乳腺癌中，BRD7通过依赖其溴结构域的AKT途径抑制MDM2的磷酸化来稳定p53，从而发挥肿瘤抑制作用。
