WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia

Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed The most common form of liver cancer is hepatocellular carcinoma (HCC) The WW domain containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia inducible factor la (HIF l alpha) levels and function Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development WWOX liver specific knockout mice (Wwox(Delta Hep)) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates Moreover, WWOX deficiency in hepatocytes combined with diethylmtrosamine treatment increased the tumor burden, which was associated with increased HI FI alpha Ylevels and target gene transactivation Inhibition of HI FI alpha by systemic treatment with digoxin significantly delayed HCC formation Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.