HDAC11 Deacetylates BRAF to Regulate Kinase Activity and Cell Proliferation.

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Histone acetylation, regulated by histone deacetylases (HDACs), is crucial in cell biology.
• Increased HDAC expression correlates with poor prognosis in diseases like cancer, highlighting the therapeutic potential of HDAC inhibitors.
• HDAC11, a less-studied isoform, uniquely modifies both acetylation and fattyacylation, suggesting broad cellular functions.

Purpose of the Study:

• To identify non-histone substrates of HDAC11 using proteomics-based mutant trapping.
• To elucidate the specific cellular events regulated by HDAC11 activity.
• To understand the role of HDAC11 in cancer signaling pathways.

Main Methods:

• Proteomics-based mutant trapping was employed to discover HDAC11 substrates.
• Follow-up studies were conducted to validate identified substrates and their functional consequences.
• BRAF kinase was investigated as a specific non-histone substrate of HDAC11.

Main Results:

• Proteomics analysis identified 64 putative non-histone substrates for HDAC11.
• HDAC11 was found to deacetylate BRAF kinase at lysine residue 680 (K680).
• This deacetylation by HDAC11 suppresses BRAF kinase activity and reduces cancer cell proliferation.

Conclusions:

• HDAC11 plays a significant role in regulating non-histone protein function, extending beyond its canonical role in histone modification.
• HDAC11-mediated deacetylation of BRAF kinase impacts cancer cell proliferation and signaling pathways.
• These findings underscore the diverse regulatory functions of HDAC11 and its potential as a therapeutic target in cancer.