Inactivation of Von-Hippel Lindau (VHL) tumor suppressor gene accounts to over ninety percent of clear renal cell carcinoma (ccRCC) cases. VHL loss results in constitutive activation of hypoxia inducible factor 2 alphas (HIF2αs), and results in HIF2α-dependent reprogramming of cancer cell metabolism. Cells with active HIF2αs become glutamine addicted. Cancer cells rely on glutamine carbons as key source to generate energy, biomass and reducing equivalents and restore the Acetyl CoA pool.
Targeting Glutaminase 1 (GLS1), the obligatory enzyme that catalyzes the first step of exogenous glutamine utilization, kills preferentially VHL-null and HIF2α-expressing cells. We test the hypothesis that Acetyl CoA Synthetase 2 (ACSS2), an enzyme that converts free acetate to Acetyl CoA, may synergize with GLS1 inhibitors to suppress growth of ccRCC. We examine with genetic and metabolic experiments the role of ACSS2 in RCC biology.
Inhibition of GLS1 decreases cellular Acetyl CoA. We showed that GLS1 inhibitor (CB-839) reduces Histone3 Lysine27 Acetylation (H3K27Ac) in vitro, preferentially in VHL-depleted cells, compared to their VHL-replete counterparts.
Preliminary experiments using an ACSS2 inhibitor support the hypothesis. We identified that nuclear ACSS2 recaptures free nuclear acetate and exogenous acetate as substrate to maintain nuclear Acetyl CoA pool for histone reacetylation in HIF2α-dependent manner.