Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development

Abstract

Hepatoblastoma (HB) is the most common type of liver malignancy in children. Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin). However, how YAP regulates HB development remains poorly defined. Similarly, de-regulation of mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in multiple tumor types, but its functional role in HB development is scarcely understood. In the present study, we found that mTORC1 is activated in human HB cells and YAP/β-catenin-induced mouse HB tumor tissues. mTOR inhibitor MLN0128 significantly inhibits human HB cell growth in vitro. Furthermore, ablation of Raptor, the unique subunit of mTORC1, strongly delayed YAP/β-catenin-induced HB development in mice. At the molecular level, we found that expression of the amino acid transporter SLC38A1 is induced in mouse HB tissues, and amino acid deprivation leads to mTORC1 suppression in HB cell lines. Silencing of YAP and/or its paralog, transcriptional co-activator with PDZ binding motif (TAZ), decreased SLC38A1 expression as well as mTORC1 activation in HB cells. Furthermore, a frequent and concomitant upregulation of mTORC1 and SLC38A1 was detected in a collection of human HB specimens. Altogether, our study demonstrates the key role of mTORC1 in HB development. YAP and TAZ promote HB development via inducing SLC38A1 expression, whose upregulation leads to mTORC1 activation. Targeting mTOR pathway or amino acid transporters may represent novel therapeutic strategies for the treatment of human HB.

TEA Domain Transcription Factor 4 Is the Major Mediator of Yes-Associated Protein Oncogenic Activity in Mouse and Human Hepatoblastoma

“…28 More important, we have recently shown that YAP is activated in both HB cell lines. 31 In light of this body of information, dnTEAD2 was overexpressed in HepG2 and Hep293TT cells. As expected, dnTEAD2 effectively inhibited the expression of Yap downstream targets, such as cysteine-rich angiogenic inducer 61 (CRY61), connective tissue growth factor (CTGF ), AXL receptor tyrosine kinase (AXL), and baculoviral IAP repeat containing 5 (BIRC5, alias SURVIVIN) in HepG2 and Hep293TT cells (Supplemental Figure S1A).…”

CDK9 is dispensable for YAP‐driven hepatoblastoma development

“…However, targeting GOF CTNNB1 mutations is particularly challenging. Besides β‐catenin, previous data indicate the YAP pathway as a potentially important target for the treatment of HB 12,22,23 . Recently, it was found that YAP regulates gene transcription through its interaction with the mediator/CDK9 complex 21 .…”

“…The plasmids used in this study, including pT3‐EF1α‐∆N90‐β‐catenin, pT3‐EF1α‐YAPS127A, pT3‐EF1α‐GFP‐shLuc (where Luc is luciferase), and pCMV sleeping beauty (SB) transposase, have been described previously 22,23 . The pT3‐EF1α‐GFP‐shCdk9 construct was a generous gift from Dr. Chun‐Hao Huang from the Memorial Sloan‐Kettering Cancer Center (New York, NY).…”

“…The plasmids used in this study, including pT3-EF1 -∆N90--catenin, pT3-EF1 -YAPS127A, pT3-EF1 -GFP-shLuc (where Luc is luciferase), and pCMV sleeping beauty (SB) transposase, have been described previously. 22,23 The pT3-EF1 -GFP-shCdk9 construct was a gener-…”

Animal Modeling of Pediatric Liver Cancer

“…More recent work further showed the utility of this model. In 2017, the CTNNB1/Yap-1 model was combined with liver-specific Raptor knock-out to show a role of mammalian target of rapamycin complex 1 (mTORC1) signaling downstream of YAP-1 in HB [51]. In a second paper from 2017, Yamamoto and colleagues used the hydrodynamic tail vein injection/Sleeping Beauty transposon model to overexpress myc, Yap-1, AKT, Notch1, and Notch2 alone and in combination to generate tumors resembling HB, HCC, and cholangiocarcinoma [52].…”