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.
基金：
NIH [R35CA253027, CA177910, CA183914]; National Natural Science Foundation of China [81972558]; Natural Science Foundation of Jilin [20200201367JC]; ACS grants; FORMA Therapeutics, Inc.
第一作者单位：[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
通讯作者：
通讯机构：[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
推荐引用方式(GB/T 7714)：
Dai Xiangpeng,Zhang Xiaoling,Yin Qing,et al.Acetylation-dependent regulation of BRAF oncogenic function[J].CELL REPORTS.2022,38(3):doi:10.1016/j.celrep.2021.110250.
生物学