Background and Aims Proteins that recognize epigenetic modifications function as mediators to interpret epigenetic codes. Hypoxia response and metabolic rewiring are two major events during cancer progression. However, whether and how the epigenetic regulator integrates hypoxia response and metabolism together remain open for study. Approach and Results We data mined the clinical association of 33 histone lysine acetylation reader proteins with liver cancer and found that ALL1‐fused gene from chromosome 9 (AF9) is up‐regulated 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 proto‐oncogene/β‐catenin. Loss of AF9 heavily impaired cell proliferation and completely blocked solid tumor formation. We further discovered that AF9 formed a positive feedback circuit with hypoxia‐inducible factor 1 alpha (HIF1α) and also stabilized MYC proto‐oncogene (cMyc). Mechanically, AF9 interacted with HIF1α and targeted HIF1A promoter whereas AF9 recognized cMyc acetylation at K148, protected cMyc phosphorylation at S62, and then stabilized cMyc, which, in turn, up‐regulates phosphofructokinase, platelet expression. Otherwise, knockout of Af9 in mouse hepatocytes increased the infiltration of CD8+ T cells, which is linked to the down‐regulation of lactate dehydrogenase A. Conclusions AF9 is up‐regulated 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 drugs against liver cancer.