Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma

Abstract Background & Aims Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying mechanisms remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor via mTORC1 axis. Methods We performed qRT-PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor suppressive function of VEPH1. Results VEPH1 is frequently silenced in HCC tissues, primarily resulted from let-7d up-regulation. Decreased VEPH1 expression is associated with poor prognosis of HCC patients, and aggressive tumor phenotypes. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. VEPH1 (580-625aa) and VEPH1 (447-579aa) directly bind to TSC1 (719-1164aa) and TSC2 (1-420aa), respectively, to enhance the association between TSC1 and TSC2, an effect increases TSC2 Ser1387 phosphorylation through concentration at membrane. Subsequently, Rheb GAP activity is increased, leading to antagonized mTORC1 signaling. Outputs downstream of mTORC1 including S6K1, rpS6, 4E-BP1, and epithelial-mesenchymal transition (EMT) process, all contributes to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1-knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser1387 phosphorylation and increased mTOR activity in HCC specimens. Conclusions The loss of VEPH1 unleashes mTORC1 signaling activity in HCC, and that rapamycin (or rapalogs) may serve as an effective therapeutic drug for HCC patients with dampened VEPH1 expression.