Acetylation-dependent regulation of BRAF oncogenic function

被引：17

作者：

Dai, Xiangpeng ^{[1
,2
,3
]}

Zhang, Xiaoling ^{[2
,3
]}

Yin, Qing ^{[4
]}

Hu, Jia ^{[1
,5
]}

Guo, Jianping ^{[1
,6
]}

Gao, Yang ^{[1
,7
]}

Snell, Aidan H. ^{[4
]}

Inuzuka, Hiroyuki ^{[1
]}

Wan, Lixin ^{[4
]}

Wei, Wenyi ^{[1
]}

机构：

[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[2] First Hosp Jilin Univ, Minist Educ, Lab Organ Regenerat & Transplantat, Changchun 130061, Peoples R China

[3] Natl Local Joint Engn Lab Anim Models Human Dis, Changchun 130061, Jilin, Peoples R China

[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, 12902 USF Magnolia Dr, Tampa, FL 33612 USA

[5] Huazhong Univ Sci & Technol, Dept Urol, Tongji Hosp, Tongji Med Coll, Liberalizat Ave 1095, Wuhan 430030, Peoples R China

[6] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou 510275, Peoples R China

[7] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Urol, Xian 710061, Peoples R China

来源：

CELL REPORTS | 2022年 / 38卷 / 03期

基金：

中国国家自然科学基金;

关键词：

CELL-CYCLE; HISTONE ACETYLTRANSFERASE; KINASE; ACTIVATION; PHOSPHORYLATION; MUTATIONS; TRANSCRIPTION; INHIBITOR; DISCOVERY; POTENT;

D O I：

10.1016/j.celrep.2021.110250

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Aberrant BRAF activation, including the BRAF(V600E) mutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAF(V600E) inhibitor resistance in BRAF(V600E) harboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1 deficiency as potential biomarkers to determine ERK activation in melanomas.

引用

页数：16

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