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Updated: Oct 6, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Acetylation-dependent regulation of BRAF oncogenic function

Xiangpeng Dai1, Xiaoling Zhang2, Qing Yin3

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, PR China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130061, PR China.

Cell Reports
|January 19, 2022
PubMed

Insights

Acetylation by p300 activates BRAF kinase, promoting cancer cell growth and drug resistance. This acetylation is reversed by SIRT1, offering new biomarkers for melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Aberrant BRAF activation, particularly the BRAFV600E mutation, is common in cancers.
  • Regulation of BRAF kinase activity beyond phosphorylation and ubiquitination is not well understood.

Purpose of the Study:

  • To investigate the role of post-translational modifications, specifically acetylation, in BRAF kinase regulation.
  • To identify the enzymes involved in BRAF acetylation and deacetylation and their impact on cancer.

Main Methods:

  • Investigated BRAF K601 acetylation using biochemical assays.
  • Assessed the effects of p300 (acetyltransferase) and SIRT1 (deacetylase) on BRAF activity.
  • Utilized patient-derived mutations and cell proliferation assays.

Main Results:

  • p300 acetylates BRAF at K601, activating its kinase activity.
  • SIRT1 antagonizes p300-mediated BRAF K601 acetylation.
  • K601 acetylation promotes BRAF dimerization and enhances melanoma cell proliferation.
  • K601 acetylation contributes to resistance against BRAFV600E inhibitors.
  • A patient-derived K601E mutation mimics acetylation to increase BRAF activity.

Conclusions:

  • Uncovered a novel acetylation-dependent regulatory mechanism for BRAF kinase.
  • p300-mediated K601 acetylation is a key driver of melanoma proliferation and drug resistance.
  • p300 hyperactivation or SIRT1 deficiency may serve as biomarkers for ERK activation in melanoma.
Keywords:
BRAFSIRT1acetylationmelanomap300

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