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Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma
Pingping Dong1, Xiaoxiao Wang2, Longzi Liu3
1Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Surgery, Centre for Cancer Research, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Background & Aims:
Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis.
Methods:
We performed quantitative reverse-transcription 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 resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser1387 phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing 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 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression.
Lay Summary:
Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.
Insights
Ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) acts as a tumor suppressor in hepatocellular carcinoma (HCC) by inhibiting mTORC1 signaling. Loss of VEPH1 promotes HCC progression, suggesting mTOR inhibitors as a potential treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Abnormal activation of mTORC1 signaling is frequent in hepatocellular carcinoma (HCC).
- The causes of aberrant mTORC1 activation in HCC remain largely unknown.
- Ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) is identified as a novel tumor suppressor.
Purpose of the Study:
- To investigate the role of VEPH1 in hepatocellular carcinoma (HCC).
- To elucidate the mechanisms by which VEPH1 suppresses tumors via the mTORC1 axis.
- To explore VEPH1 as a potential therapeutic target in HCC.
Main Methods:
- Quantitative reverse-transcription PCR, western blot, and immunostaining were performed on HCC tissues.
- Functional effects of VEPH1 on tumor growth and metastasis were assessed in vitro and in vivo.
- Molecular and biochemical strategies were employed to understand VEPH1's tumor-suppressive mechanisms.
Main Results:
- VEPH1 is frequently silenced in HCC, often due to let-7d upregulation, and its loss correlates with poor prognosis.
- VEPH1 suppresses HCC cell proliferation, migration, and invasion by enhancing TSC1/TSC2 binding and inactivating Rheb, thereby inhibiting mTORC1.
- Rapamycin, an mTOR inhibitor, counteracts the pro-tumorigenic effects of VEPH1 knockdown in HCC.
Conclusions:
- Loss of VEPH1 leads to aberrant mTORC1 activation in HCC, contributing to tumorigenesis and metastasis.
- Rapamycin or rapalogs show potential as effective treatments for HCC patients with reduced VEPH1 expression.
- Low VEPH1 expression is a potential driver of activated mTOR signaling in HCC, supporting mTOR inhibitors as a therapeutic strategy.
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