Yun-Yong Park 1 , 2 , 3 , Bo Hwa Sohn 1 , 2 , Randy L. Johnson 4 , Myoung-Hee Kang 3 , Sang Bae Kim 1 , 2 , Jae-Jun Shim 1 , 2 , 5 , Lingegowda S. Mangala 6 , 7 , Ji Hoon Kim 8 , Jeong Eun Yoo 9 , Cristian Rodriguez-Aguayo 7 , 10 , Sunila Pradeep 6 , Jun Eul Hwang 1 , 2 , Hee-Jin Jang 1 , 2 , Hyun-Sung Lee 1 , 2 , Rajesha Rupaimoole 6 , Gabriel Lopez-Berestein 7 , 10 , Woojin Jeong 11 , Inn Sun Park 1 , Young Nyun Park 9 , Anil K. Sood 6 , 7 , 12 , Gordon B. Mills 1 , 2 , Ju-Seog Lee 1 , 2
26 November 2015
Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma (HCC). Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. YAP1 and TAZ are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/ TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters SLC38A1 and SLC7A5. Subsequently, increased uptake of amino acids by the transporters activates mTORC1, a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in HCC patients. Furthermore, inhibition of the transporters and mTORC1 significantly block YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism’s potential clinical implications for treating HCC.