Abstract
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway, which ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined. Here it is demonstrated that S1P activates YAP and that the S1P receptor 2 (S1PR2/S1P2) mediates S1P-induced YAP activation in both human and mouse HCC cells. S1P promotes YAP-mediated upregulation of cysteine-rich protein 61 and connective tissue growth factor (CTGF), and stimulates HCC cell proliferation. By using siRNA-mediated knockdown approaches, only CTGF was required for S1P-stimulated cell proliferation. Of note, S1P activates YAP in a MST1/2-independent manner suggesting that the canonical Hippo kinase is not required for S1P-mediated proliferation in liver. The upregulation of CTGF and S1P2 were also observed in liver-specific YAP overexpression transgenic mouse hepatocytes. Moreover, YAP regulated liver differentiation-dependent gene expression by influencing the chromatin binding of HNF4α based on ChIP-seq analysis. Finally, results using gain- and loss-of-function approaches demonstrate that HNF4α negatively regulated S1P-induced CTGF expression.Implications: These findings reveal a role for S1P in stimulating HCC cell proliferation by upregulating CTGF expression through S1P2-mediated YAP activation. Mol Cancer Res; 16(10); 1543-55. ©2018 AACR.
Highlights
Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer-related deaths worldwide [1]
Implications: These findings reveal a role for S1P in stimulating HCC cell proliferation by upregulating connective tissue growth factor (CTGF) expression through S1P receptor 2 (S1P2)-mediated YAP activation
Using pharmacologic antagonists and agonists as well as specific siRNAs, our results demonstrate that S1P2 is involved in S1P-induced activation of YAP, and YAP activation is required for S1P-stimulated HCC cell proliferation
Summary
Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer-related deaths worldwide [1]. The lethality of this disease is primarily due to late diagnosis and a paucity of therapeutic options. Partial hepatectomy is currently the most common first-line therapy for patients with HCC. The liver has a remarkable regenerative capacity and is able to rapidly restore its original weight and size after partial hepatectomy. The Hippo pathway was first identified in Drosophila and is a critical regulator of organ size [2]. Hippo pathway activation leads to stimulation of the serine/threonine kinases MST1/2, which phosphorylate the downstream kinases LATS1/2
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