Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

Abstract

BaCKgRoUND aND aIMS: Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. appRoaCH aND ReSUltS: We generated a mouse model allowing conditional activation of MYC and WNT/ β-catenin signaling (through either β-catenin activation or loss of APC-adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma

“…MYC has been shown to be a target of b-catenin; however, as shown in a recent study, 21 there was no correlation between transposon-driven CTNNB1 mRNA levels and levels of MYC or MYC targets ( Figure 5A; Supplementary Figure 5A). Surprisingly, there was a significant positive correlation between transposon-driven MYC mRNA levels and b-catenin canonical targets, whereas there was no correlation with b-catenin liver-specific targets ( Figure 5A; Supplementary Figure 5A).…”

“…In a recent study, MYC and b-catenin were shown to cooperate in HCC through the Hippo pathway. 21 We previously showed that cooperation between MYC and b-catenin promotes immune escape and resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy in an immunogenic mouse model of HCC, 14 a result that has been validated in patients. 19,25 In the current study, several of the models, including MYC;CTNNB1 with high levels of MYC, presented tumors that were enriched in the "immune class" signature, 19 which is present in human HCC tumors that could potentially respond to immunotherapies.…”

Yes-Associated Protein 1: Role and Treatment Prospects in Orthopedic Degenerative Diseases

“…In recent years, research on YAP1 has increased, especially with respect to tumors. YAP1 has been confirmed to be overexpressed in a variety of tumors, including gastric tumors ( An et al, 2020 ), liver tumors ( Bisso et al, 2020 ), ovarian cancer ( Munoz-Galvan et al, 2020 ), and breast cancer ( Song et al, 2018 ), suggesting that YAP1 has a role as a candidate oncogene in tumorigenesis. In addition, YAP1 also plays an important role in the migration and invasion of melanoma and osteosarcoma ( Zucchini et al, 2019 ; Luo et al, 2020 ).…”

N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets

“…Previous studies reported YAP as a crucial oncogene in HCC development ( 39 – 41 ). Moreover, Andrea Bisso et al., demonstrated that YAP mediated the cooperation between MYC and β-Catenin and facilitated liver tumorigenesis ( 42 ). Wenbo Ma et al., also found that histone methyltransferase G9a promoted cholangiocarcinogenesis via YAP ( 43 ).…”