HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Activating K-RAS mutations are prevalent in lung, colon, and pancreatic cancers, correlating with poor therapeutic outcomes.
• Targeting K-RAS posttranslational modifications presents a strategy to overcome resistance to current therapies.
• While farnesylation inhibition failed, other modifications like acetylation remain promising targets.

Purpose of the Study:

• To investigate the role of K-RAS acetylation in cancer cell transformation.
• To identify the specific deacetylases regulating K-RAS acetylation.
• To evaluate the therapeutic potential of targeting these deacetylases in K-RAS-mutant cancers.

Main Methods:

• Assessed K-RAS acetylation at lysine 104.
• Identified HDAC6 and SIRT2 as key regulators of K-RAS acetylation.
• Inhibited HDAC6 and/or SIRT2 in cancer cells expressing mutant K-RAS.
• Monitored the impact of inhibition on cancer cell growth properties.

Main Results:

• Acetylation of K-RAS at lysine 104 was shown to attenuate its transforming activity by disrupting GEF-induced nucleotide exchange.
• HDAC6 and SIRT2 were identified as the primary deacetylases controlling K-RAS acetylation in cancer cells.
• Inhibition of HDAC6 or SIRT2 significantly affected the growth of cancer cells harboring K-RAS mutations.

Conclusions:

• Altering K-RAS acetylation is a viable approach to mitigate its tumorigenic potential.
• Targeting HDAC6 and/or SIRT2 represents a novel therapeutic strategy for K-RAS-mutant cancers.