Yes‐associated protein 1 and transcriptional coactivator with PDZ‐binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma

Abstract

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. Conclusion YAP1 and TAZ regulate cancer metabolism and mTOCR1 through regulation of amino acid transportation and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets.

The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

“…Because LAT1 is a high-affinity amino acid transporter and solid tumors often experience nutrient limitation due to insufficient blood supply, elevated LAT1 in tumor cells, potentially due to mutations in the Hippo pathway, will gain the upper hand in competing with surrounding wildtype cells for nutrients. Therefore, targeting either YAP/ TAZ and/or LAT1 (CD98) may be an attractive therapeutic target in treating YAP/TAZ-driven cancers [2,4,50,[53][54][55][56][57][58][59]. The finding that YAP/TAZ regulate SLC7A5 expression and LAT1 activity to activate mTORC1 is consistent with a recent report [50], and together these studies represent an important step in understanding how YAP/TAZ target genes promote cell growth and how these potent growth regulatory pathways are interconnected.…”

“…Cells and organisms must adjust to fluctuating nutrient levels, especially during development and regeneration [2,47,48]. Crosstalk between potent cellular growth pathways, such as the Hippo and mTOR pathways, on multiple levels is crucial to maintain homeostasis [1,45,[49][50][51][52]. This report shows that cells with high YAP/TAZ activity gain an enhanced ability of acquiring nutrients to support biosynthesis and growth.…”

The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

“…Although we are unable to rule out GLS2 regulation, GLS was previously identified as a transcriptional target of YAP and TAZ in pulmonary hypertension (78), suggesting this more widely expressed form of glutaminase (37) may be targeted by YAP/TAZ in multiple disease contexts. Additional YAP targets in glutamine metabolism include glutamine synthetase (GLUL) and the glutamine transporter SLC38A1 in liver cancer (79, 80), implying the EphA2-YAP/TAZ signaling axis may enhance glutamine metabolism through many gene targets. However, in the context of breast cancer, transcriptional regulation of the more catalytically-active glutaminase isoform, GAC , by TAZ supports the tumor-promoting properties associated with EphA2 and YAP/TAZ overexpression.…”

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

“…Moreover, WNT signaling can stabilize YAP to potentiate its downstream effects, through upregulation of TRIB2, which downregulates a ubiquitin ligase that normally targets YAP for degradation 116 . Additionally, in certain subtypes of HCC, loss of Hippo signaling correlates with mTOR pathway activation 117, 118 , which is thought to proceed through activation of the PI3K pathway via a YAP-induced microRNA that reduces expression of PTEN 119 . YAP has also been shown to activate the mTOR pathway through the upregulation of amino acid transporters, SLC38A1 and SLC7A5 118 .…”

“…Additionally, in certain subtypes of HCC, loss of Hippo signaling correlates with mTOR pathway activation 117, 118 , which is thought to proceed through activation of the PI3K pathway via a YAP-induced microRNA that reduces expression of PTEN 119 . YAP has also been shown to activate the mTOR pathway through the upregulation of amino acid transporters, SLC38A1 and SLC7A5 118 . This mechanism, in part, sustains YAP1-mediated proliferation of HCC cells.…”