Endogenous retroelement activation by epigenetic therapy reverses the Warburg effect and elicits mitochondrial-mediated cancer cell death. Scientific Publication

Abstract

During millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms.

Modern anti-cancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing anti-viral responses that eliminate tumors through mechanisms not completely understood. Here we find that massive binding of epigenetically-activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling.

Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis.

To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2-family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics.

CITATION Cancer Discov. 2021 May;11(5):1268-1285. doi: 10.1158/2159-8290.CD-20-1065. Epub 2020 Dec 18.