PLEKHG5 is stabilized by HDAC2-related deacetylation and confers sorafenib resistance in hepatocellular carcinoma

作者全名："Sha, Yu; Pan, Mingang; Chen, Yunmeng; Qiao, Liangjun; Zhou, Hengyu; Liu, Dina; Zhang, Wenlu; Wang, Kai; Huang, Luyi; Tang, Ni; Qiu, Jianguo; Huang, Ailong; Xia, Jie"

作者地址："[Sha, Yu; Pan, Mingang; Chen, Yunmeng; Liu, Dina; Zhang, Wenlu; Wang, Kai; Huang, Luyi; Tang, Ni; Huang, Ailong; Xia, Jie] Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Chongqing 400016, Peoples R China; [Sha, Yu] Henan Univ Chinese Med, Zhengzhou 450000, Peoples R China; [Qiao, Liangjun] Chongqing Med Univ, Coll Basic Med, Chongqing 400016, Peoples R China; [Zhou, Hengyu] Chongqing Med Univ, Coll Nursing, Chongqing 400016, Peoples R China; [Qiu, Jianguo] Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Chongqing 400016, Peoples R China"

通信作者："Huang, AL; Xia, J (通讯作者)，Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Chongqing 400016, Peoples R China.; Qiu, JG (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Chongqing 400016, Peoples R China."

来源：CELL DEATH DISCOVERY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000997224700001

JCR分区：Q2

影响因子：7

年份：2023

卷号：9

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Sorafenib is the first FDA-approved first-line targeted drug for advanced HCC. However, resistance to sorafenib is frequently observed in clinical practice, and the molecular mechanism remains largely unknown. Here, we found that PLEKHG5 (pleckstrin homology and RhoGEF domain containing G5), a RhoGEF, was highly upregulated in sorafenib-resistant cells. PLEKHG5 overexpression activated Rac1/AKT/NF-kappa B signaling and reduced sensitivity to sorafenib in HCC cells, while knockdown of PLEKHG5 increased sorafenib sensitivity. The increased PLEKHG5 was related to its acetylation level and protein stability. Histone deacetylase 2 (HDAC2) was found to directly interact with PLEKHG5 to deacetylate its lysine sites within the PH domain and consequently maintain its stability. Moreover, knockout of HDAC2 (HDAC2 KO) or selective HDAC2 inhibition reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vitro and in vivo, while overexpression of PLEKHG5 in HDAC2 KO cells reduced the sensitivity to sorafenib. Our work showed a novel mechanism: HDAC2-mediated PLEKHG5 posttranslational modification maintains sorafenib resistance. This is a proof-of-concept study on targeting HDAC2 and PLEKHG5 in sorafenib-treated HCC patients as a new pharmaceutical intervention for advanced HCC."

基金机构："National Natural Science Foundation of China [81602045, 81802454, U20A20392]; Science and Technology Research Program of Chongqing Education Commission [KJQN202100424]; 111 Project [D20028]; Natural Science Foundation Project of Chongqing [cstc2018jcyjAX0825]"

基金资助正文："We thank Professor Yujun Shi (Sichuan University, Chengdu, China) and Dr. Yongjie Zhou (Sichuan University, Chengdu, China) who kindly supplied the HDAC2LKO mice. We also thank Dr. Fanghui Lu (Chongqing Medical University, Chongqing, China) for technical suggestions and language editing. This work was supported by grants from the National Natural Science Foundation of China (no. 81602045; no. 81802454; no. U20A20392), the Science and Technology Research Program of Chongqing Education Commission (no. KJQN202100424), the 111 Project (no. D20028), and the Natural Science Foundation Project of Chongqing (no. cstc2018jcyjAX0825)."