The H3 ^K36M oncohistone inhibits NSD2 to activate a SETD2-dependent antiviral-like immune response in KRAS-driven lung cancer

Mutations in histone 3 at or near lysine 36 (H3K36) have dominantly acting oncogenic effects in multiple tumor types by limiting H3K36-directed methyltransferases. Paradoxically, we find that expression of the H3 ^K36M oncohistone unexpectedly inhibits tumor formation in KRAS-driven lung adenocarcinoma by inducing a potent immune-mediated tumor clearance. Mechanistically, oncohistone expression derepresses endogenous retroviral element transcription, results in the accumulation of double-stranded RNA (dsRNA), and activates an innate antiviral-like immune response that eradicates tumor growth. Surprisingly, while inactivation of the H3K36 di-methyltransferase NSD2 replicated all effects of oncohistone expression, inactivation of the H3K36 tri-methyltransferase SETD2 abolished element derepression and all associated downstream anti-cancer effects that are induced by oncohistone expression. These observations restructure our understanding of the roles of H3K36 methylation, the consequences of its deregulation in cancer, and shape our expectations for therapeutic interventions targeting H3K36 methyltransferases.