mTOR/HDAC1 Crosstalk Mediated Suppression of ADH1A and ALDH2 Links Alcohol Metabolism to Hepatocellular Carcinoma Onset and Progression in silico

Abstract

Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC.

Keywords: ADH1A; ALDH2; alcohol metabolism; hepatocellular carcinoma; mTOR signaling; metabolic imbalance; tumor progression.