HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Clear cell renal cell carcinoma (ccRCC) is driven by VHL loss and aberrant HIF-2α signaling.
• ACSS2, involved in acetate metabolism, is linked to poor ccRCC prognosis.
• Regulating HIF-2α presents a therapeutic opportunity for ccRCC.

Purpose of the Study:

• To investigate the effects of ACSS2 inhibition on HIF-2α and ccRCC progression.
• To elucidate the mechanisms by which ACSS2 influences HIF-2α stability and cancer metabolism.
• To explore ACSS2 inhibition as a complementary therapy for ccRCC.

Main Methods:

• Utilized ccRCC cell lines, in vivo models, and primary patient tumor cultures.
• Assessed the impact of ACSS2 inhibition on HIF-2α levels, cell growth, and metabolic pathways.
• Investigated the interaction between ACSS2, HIF-2α, and the E3 ligase MUL1.

Main Results:

• ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell growth across models.
• Treatment decreased glycolytic signaling, cholesterol metabolism, and mitochondrial integrity.
• ACSS2 inhibition affected chromatin accessibility, impacting HIF-2α expression and stability.
• Identified a pVHL-independent degradation pathway for HIF-2α involving MUL1, partially dependent on ACSS2.

Conclusions:

• ACSS2 inhibition effectively reduces HIF-2α levels and ccRCC tumor growth.
• ACSS2 plays a role in regulating HIF-2α stability through both pVHL-dependent and independent pathways.
• Targeting ACSS2 is a promising strategy to complement existing HIF-2α-targeted therapies in ccRCC.