The transcriptional coactivator AF9 simultaneously sustains hypoxia tolerance and metabolic advantages in liver cancer.

Proteins that recognize the epigenetic modifications function as mediators to interpret the epigenetic codes. Hypoxia response and metabolic rewiring are two major events during cancer progression. However, it's still unclear whether and how epigenetic regulator integrates hypoxia response and metabolism together. We data mined the clinical association of 33 histone Kac reader proteins with liver cancer and that AF9 is upregulated in cancer and correlates with tumor stage and poor prognosis. Conditional deletion of Af9 in mouse liver resulted in decreased tumor formation induced by c-Met/β-catenin. Loss of AF9 heavily impaired cell proliferation and completely blocked solid tumor formation. We further discovered AF9 formed a positive feedback circuit with HIF1α and also stabilized cMyc. Mechanically, AF9 interacted with HIF1α and targeted HIF1A promoter while AF9 recognized cMyc acetylation at K148, protected cMyc phosphorylation at S62 and then stabilized the cMyc which in turn upregulates PFKP expression. Otherwise, knockout of Af9 in mouse hepatocyte increased the infiltration of CD8+ T cells which is linked to the downregulation of LDHA. In conclusions, AF9 is upregulated to promote gene expression of hypoxia tolerance and glycolysis by simultaneously forming a complex with HIF1α and recognizing acetylated cMyc. Our results establish the oncogenic role of AF9 in human liver cancer, which could be a potential target for designing novel drugs against liver cancer.