Abstract
The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant pathways that regulate tumour growth and metastasis. Therefore, we explored the potential crosstalk between these two functionally relevant pathways to coordinate their tumour growth-control functions. We found that a Hippo pathway-related long noncoding RNA, HPR, directly interacts with Raptor, an essential component of mTORC1, to upregulate mTORC1 activation by impairing the phosphorylation of Raptor by AMPK. Knockdown or knockout of HPR in breast cancer and cholangiocarcinoma cells led to a reduction in tumour growth. Compared with HPR WT cells, HPR-overexpressing cells exhibited nuclear accumulation of YAP1, and significantly blocked the downregulation of mTORC1 signalling induced by energy stress. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways in the control of tumour growth.
Highlights
Cancer is the consequence of dysregulated signalling pathways
These results demonstrate that hippo pathway-related lncRNA (HPR) may promote tumour growth through coactivation of YAP and mammalian target of rapamycin complex 1 (mTORC1) and that targeting the HPR using locked nucleic acids (LNAs) can suppress breast cancer in a preclinical model (Fig. 7d and Supplement Fig. 5)
Our findings demonstrate that lncRNAs coregulate both the YAP1 and mTORC1 pathways in cancer
Summary
Cancer is the consequence of dysregulated signalling pathways. Dissecting the molecular mechanisms of cancer signalling pathways lays the foundation for developing targeted cancer therapies. Recent research has shown that a variety of molecular mechanisms regulate the activity of YAP/TAZ [8,9,10,11]. The negative regulatory role of AMPK could be uncoupled by unknown mechanisms, leading to hyperactivation of the YAP1 pathway. The mammalian target of rapamycin (mTOR) signalling pathway has important role in regulating cell growth, metabolism and survival. MTORC1 plays essential roles in promoting cell growth and proliferation by regulating protein biosynthesis, autophagy, lipid biogenesis, mitochondrial metabolism and other pathways. LncRNAs have been demonstrated to play important roles in modulating cancer signalling pathways through RNA–protein interactions [11, 26,27,28,29,30]. Our research work demonstrates a lncRNA directed molecular mechanism for coactivation of the Hippo and mTORC1 pathways in cancer
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