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HDAC Inhibitor-Induced Acetylation of KRAS Confers A Pro-Oncogenic Effect Limiting Treatment Response in Colorectal Cancer

ABSTRACT: The limited clinical utility of HDAC inhibitors for the treatment of colorectal cancer (CRC) has until now remained an unresolved conundrum. Our findings provide comprehensive mechanistic insight into the ineffectiveness that defines HDAC inhibitors as a monotherapy for CRC. We identified that inhibition of HDAC2 promotes the emergence of a super-oncogenic KRAS by inducing K5 acetylation that fosters a previously undiscovered electrostatic interaction with R67 conserved in RAF kinases. This post-translational modification facilitates an increase in the binding affinity to this family of downstream RAS effectors, which translates into an immediate and persistent hyperactivation of the downstream MAPK-signaling. The concomitant instability of its co-conspirator c-MYC enables cells selectively harboring oncogenic KRAS to enter a protective state of reversible cell cycle arrest characterized by a senescence-like phenotype. Demonstratively, preventing this phenomenon from taking place provides a compelling alternative strategy for improving the prospects of HDAC inhibitor treatment for CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108191 | GEO | 2019/03/31

REPOSITORIES: GEO

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