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

Tumors adapt to hypoxic environments by activating stress-responsive transcriptional programs; however, the chromatin structure permitting these adaptations is poorly defined. We identify ACTL6A, a SWI/SNF subunit over-expressed in several cancers, as a critical regulator of enhancer architecture that drives glycolysis and hypoxia gene expression in head and neck squamous cell carcinoma. ACTL6A expression coordinates AP-1 chromatin accessibility at enhancers while simultaneously amplifying MAPK/ERK signaling through Ras and Galectin-1. ACTL6A is required for the metabolic effects of MEK inhibitors and is strongly correlated with induction of p-ERK and MAPK signaling programs across human cancers. Depleting ACTL6A collapses hypoxic adaptation in vivo and inhibits glycolysis, leading to increased mitochondrial dependency. Using spatial biology, we define an ACTL6A-dependent transcriptional signature in human tumors that drives hypoxia and MAPK signaling and marks a spatially-isolated malignant cell niche. ACTL6A depletion induces a metabolic vulnerability in treatment resistant tumors that sensitizes them to IACS-010759 in vivo. These results implicate ACTL6A as an epigenetic switch that sustains a chromatin architecture permissive for hypoxic adaptation and metabolic plasticity, which can be exploited to target SWI/SNF-amplified tumors.