Targeting super-enhancers reprograms glioblastoma central carbon metabolism

Abstract

The concept that tumor cells demand a distinct form of metabolism was appreciated almost a century ago when the German biochemist Otto Warburg realized that tumor cells heavily utilize glucose and produce lactic acid while relatively reducing oxidative metabolism. How this phenomenon is orchestrated and regulated is only partially understood and seems to involve certain transcription factors, including c-Myc, HIF1A and others. The epigenome eintails the posttranslational modification of histone proteins which in turn are involved in regulation of transcription. Recently, it was found that cis-regulatory elements appear to facilitate the Warburg effects since several genes encoding for glycolysis and associated pathways are surrounded by enhancer/super-enhancer regions. Disruption of these regions by FDA-approved HDAC inhibitors suppressed the transcription of these genes and elicited a reversal of the Warburg effect with activation of transcription factors facilitating oxidative energy metabolism with increases in transcription factors that are part of the PPARA family. Therefore, combined targeting of HDACs and oxidative metabolism suppressed tumor growth in patient-derived xenograft models of solid tumors, including glioblastoma.