Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular Carcinoma

Targeting the Metabolic Vulnerability of ARID1A-Deficient Hepatocellular Carcinoma

“… 3 These notions contradict the findings of Zhang et al. 2 The heterogeneous context of HCC may be a possible explanation to this paradox. AMPK might serve as an oncogene in glucose-deprived HCC but acts as a tumor suppressor in other HCC subtypes.…”

“…They also demonstrated a possibility of targeting the metabolic vulnerability of ARID1A-deficient HCC cells by AMPK inhibitor. The findings of Zhang et al 2 linked the epigenetic regulatory function of ARID1A to cancer metabolism, which significantly enhances the understanding of the molecular mechanisms of ARID1A-related HCC. The findings also highlighted that ARID1A deficiency might be a potential biomarker for precision HCC treatment.…”

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , Zhang et al 2 studied the functions and therapeutic implications of ARID1A in human HCC. They found that ARID1A is frequently downregulated at the protein level and associated with shorter overall and disease-free survival rates of patients with HCC.…”

“…Thus, the identification of the ARID1A/HDAC1/USP9X/AMPK axis explained why the loss of ARID1A provided a growth advantage to HCC cells under the glucose-deprived condition. Importantly, Zhang et al 2 demonstrated a synthetic lethality between ARID1A deficiency and AMPK inactivation in HCC. Treatment of AMPK inhibitor, Compound C, suppressed HCC growth in orthotopic implantation model in nude mice.…”

“…Interestingly, ARID1A knockout cells were more sensitive to Compound C treatment and exhibited a prolonged survival of tumor-bearing mice. Thus, Zhang et al 2 delineated a novel ARID1A/HDAC1/USP9X/AMPK axis that might be important for HCC development and progression. They also demonstrated a possibility of targeting the metabolic vulnerability of ARID1A-deficient HCC cells by AMPK inhibitor.…”