HDAC8 Enhances the Function of HIF-2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Drug resistance to Tyrosine kinase inhibitors (TKIs) limits survival in clear cell renal cell carcinoma (ccRCC).
• Understanding the mechanisms of acquired resistance is crucial for developing effective ccRCC therapies.

Purpose of the Study:

• To identify novel targets involved in ccRCC resistance to TKIs.
• To elucidate the molecular mechanisms underlying HDAC8's role in TKI resistance.
• To develop strategies to overcome TKI resistance in ccRCC.

Main Methods:

• Genome-wide CRISPR-based screening to identify resistance-associated genes.
• Molecular assays to investigate protein interactions and post-translational modifications (acetylation, phosphorylation).
• Synthesis and evaluation of HDAC8-based Proteolysis Targeting Chimeras (PROTACs).

Main Results:

• HDAC8 was identified as a key mediator decreasing ccRCC sensitivity to sunitinib.
• HDAC8 promotes TKI resistance by deacetylating ETS1, enhancing ETS1/HIF-2α complex activity.
• HDAC8 inhibition upregulates NEK1, which further promotes ETS1/HIF-2α interaction.
• TKI treatment increases HDAC8 expression via STAT3 inhibition, contributing to acquired resistance.
• HDAC8-in-PROTACs were synthesized to degrade HDAC8 and overcome TKI resistance.

Conclusions:

• HDAC8 plays a critical role in acquired resistance to TKIs in ccRCC.
• Targeting HDAC8, particularly through PROTACs, presents a promising therapeutic strategy for overcoming TKI resistance in ccRCC.
• HDAC8 is a potential therapeutic candidate for ccRCC-targeted therapies.