Inhibition of GSK3 and TSC2 Mediates the Oncogenic Activity of AKT in Hepatocellular Carcinoma

Abstract Aberrant activation of AKT is a key oncogenic driver in hepatocellular carcinoma (HCC). As AKT activates multiple downstream signaling pathways, the key mechanisms mediating AKT-driven tumorigenesis must be elucidated to develop optimal treatment strategies. Using an Akt/NRas-induced HCC mouse model, we found that AKT promotes tumorigenesis by targeting tuberous sclerosis complex 2 (TSC2) and glycogen synthase kinase 3 α/β (GSK3α/β) rather than forkhead box O protein family members. Loss of either TSC2, leading to mTORC1 activation, or both GSK3 isoforms cooperated with activated NRAS to promote HCC formation in vivo, albeit with different latencies. Simultaneous TSC2 and GSK3α/β deletion cooperated with NRAS to rapidly induce HCC formation, mirroring observations from the Akt/NRas HCC model. RNA sequencing studies indicated distinct pathways regulated by TSC2/mTORC1 and GSK3α/β during hepatocarcinogenesis, with FOXM1 functioning as a major effector of GSK3. In summary, these findings uncover AKT’s role in suppressing the TSC complex and GSK3 to drive HCC, offering mechanistic insights into oncogenic signaling and potential therapeutic targets. Significance: GSK3α/β and TSC2/mTORC1 are key downstream effectors of AKT in liver tumorigenesis that can potentially be targeted to benefit patients with hepatocellular carcinoma harboring aberrantly activated AKT.