Regulation of KDM5C stability and enhancer reprogramming in breast cancer.
Regulation of KDM5C stability and enhancer reprogramming in breast cancer.
复制标题
DOI：
10.1038/s41419-022-05296-5
复制
发表时间：
2022-10-03
影响因子：
9
通讯作者：
Wu, Min
中科院分区：
文献类型：
--
作者：
Xiao, Qiong;Wang, Chen-Yu;Gao, Chuan;Chen, Ji-Dong;Chen, Jing-Jing;Wang, Zhen;Ju, Lin-Gao;Tang, Shan-Bo;Yao, Jie;Li, Feng;Li, Lian-Yun;Wu, Min
增强子调控的异常已经成为癌细胞的关键特征之一。KDM5C是一种组蛋白H3K4去甲基化酶，在几种类型的癌症中经常发生突变。它对H3K4me3和增强子的活性至关重要，但其调控机制仍不清楚。在这里，我们将TRIM11鉴定为KDM5C的一种泛素E3连接酶。TRIM11与KDM5C相互作用，催化KDM5C上K48连接的泛素链，并通过蛋白酶体促进KDM5C降解。在动物模型中TRIM11缺陷抑制乳腺肿瘤的生长并稳定KDM5C。在乳腺癌患者组织中，TRIM11高表达，KDM5C低表达，二者表达呈负相关。从机制上讲，TRIM11通过靶向KDM5C调节参与细胞迁移和免疫应答的基因的增强子活性。TRIM11和KDM5C通过靶向MCAM增强子上的H3K4me3调节MCAM表达和细胞迁移。总之，我们的研究揭示了乳腺癌发生和发展过程中增强子调控的新机制。
Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.
登录
查看更多内容
影响因子：
10.5
作者：
Morgan MA;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
30.8
作者：
Rickels R;Herz HM;Sze CC;Cao K;Morgan MA;Collings CK;Gause M;Takahashi YH;Wang L;Rendleman EJ;Marshall SA;Krueger A;Bartom ET;Piunti A;Smith ER;Abshiru NA;Kelleher NL;Dorsett D;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
16
作者：
Roe, Jae-Seok;Mercan, Fatih;Rivera, Keith;Pappin, Darryl J.;Vakoc, Christopher R.
通讯作者：
Vakoc, Christopher R.