Epigenetic inactivation of hydroxymethylglutaryl CoA synthase reduces ketogenesis and facilitates tumor cell motility in clear cell renal carcinoma

Previously, we have reported that the dysregulation of ketogenesis plays an important role in the carcinogenesis of clear cell renal cell carcinoma (ccRCC). Here, we demonstrate decreased expression of the HMGCS2 gene in ccRCC, a critical enzyme for the synthesis of the ketone body β-hydroxybutyrate (β-OHB). We found that the reduced transcription of the HMGCS2 gene in ccRCC cells was significantly correlated to a higher relative methylation rate in its promotor region. The higher methylation rate in the region of the transcription start site and 1st exon of the HMGCS2 gene was, in turn, correlated with a worse clinical outcome for patients. The transcription of HMGCS2 was possible to restore by treatment with 5-aza-2'-deoxycytidine and with the histone deacetylase inhibitor β-OHB. Therefore, the low levels of the HMGCS2 enzyme in ccRCC may be the consequence of hypermethylation of the HMGCS2 promotor. The ensuing reduction in the ketone body levels further suppresses the transcription of HMGCS2 via a feedback loop. Ectopic expression of HMGCS2 attenuates the migration and invasion of ccRCC but does not affect the proliferative capacity of ccRCC cells in vitro. In addition, we showed that ectopic expression of HMGCS2 boosts the intracellular levels of β-OHB and that exogenously applied β-OHB suppresses the motility and invasion of ccRCC. Our study reveals crosstalk between genes that regulate metabolism and their metabolites, thus providing a better understanding of the epigenetic mechanism involved in ccRCC carcinogenesis and suggesting opportunities for metabolic therapy of tumors. Initially, we suggest that the mRNA level of HMGCS2 could serve as a potentially valuable diagnostic (AUC = 0.918, p < 0.001) and prognostic biomarker.