Analyzing the Effects of ACSS2 on Cancer Cell Growth in Patients With ccRCC

Researchers found that managing HIF-2α in patients with clear cell renal cell carcinoma (ccRCC) may have benefits.

A recent study from Zachary A. Bacigalupa, PhD, and colleagues published in the Journal of Clinical Investigation sought to determine the effects of acetyl-CoA synthetase 2 (ACSS2) on HIF-2α, cancer metabolism, and cancer growth in patients with ccRCC.

Following an investigation of ccRCC models and clinical samples, researchers noted that ACSS2 inhibition led to decreased HIF-2α levels and ccRCC cell line growth in vitro, in vivo, and in cultures from primary tumors.

Therapy with ACSS2 also demonstrated a decrease in glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, which Dr. Bacigalupa and colleagues reported was related to HIF-2α reduction. ACSS2 inhibition also led to lowered chromatin accessibility, HIF-2α expression, and stability.

Researchers noted that in a von Hippel–Lindau protein (pVHL)-dependent proteolytic degradation, HIF-2α protein levels are generally managed. They also demonstrated a possible pVHL-independent pathway of degradation from the E3 ligase MUL1.

“We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2,” Dr. Bacigalupa and colleagues stated. “These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α–targeted therapies and deplete pathogenically stabilized HIF-2α.”

Investigators concluded that ACSS2 inhibitors show potential as a therapy for patients with ccRCC.

“Taken together, our data suggest that treatment with an ACSS2 inhibitor could be effective in ccRCC patients who have a VHL mutation,” the researchers wrote. “Novel small molecules targeting ACSS2 are in development and are being characterized in preclinical models of cancer.”