ACTL6A regulates the Warburg effect through coordinated activation of AP-1 signaling in head and neck squamous cell carcinoma.

ACTL6a is an essential component of SWI/SNF and expressed on the chromosome 3q26 cytoband, which is amplified in head and neck squamous cell carcinomas (HNSCC). While ACTL6A is emerging as an oncogene, its role as a treatment target and mechanisms of transcription factor induction remain unknown. Here, we show that ACTL6A expression is a mediator of the Warburg effect, with ACTL6A knockdown inducing mitochondrial dependency and significantly decreasing levels of aerobic glycolysis. These effects lead to near complete attenuation of hypoxic cell growth by blunting induction of HIF1α and HIF2α protein expression. They also sensitize treatment resistant HNSCC cells to the tumor killing effects of the complex I inhibitor IACS-010759 in vivo. Using ATAC-seq, we identify ACTL6A as a mediator of chromatin accessibility of AP-1 transcription factor sites and find that it regulates upstream MAPK signaling through induction of Ras and Galectin-1. These effects sensitize ACTL6A over-expressing cells to inhibition of glycolysis by MEK inhibitors. Our results link SWI/SNF subunit amplification with potentiation of MAPK signaling in HNSCC and provide a novel mechanism by which cancer cells drive aerobic glycolysis and reduce mitochondrial dependency. We leverage these findings to propose treatment strategies for hypoxic tumors with SWI/SNF subunit amplifications.