Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mol Cell. 2013 Jul 25;51(2):211-25. doi: 10.1016/j.molcel.2013.05.013. Epub 2013 Jun 13.
Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.
Wnt 信号通路失调与人类肝癌的发生密切相关。然而,肝癌特异性的 Wnt 转录程序和下游效应物仍知之甚少。在这里,我们确定了 TRIB2 是肝癌中 Wnt/TCF 的直接靶标,并证明包括 TRIB2 在内的 Wnt 靶基因的转录是由肝癌细胞中的 TCF 和 FoxA 转录因子协调的。我们表明,Wnt-TRIB2 的激活对于癌细胞的存活和转化至关重要。在机制上,TRIB2 通过与βTrCP 泛素连接酶相互作用促进 YAP 转录共激活因子的蛋白质稳定。此外,我们发现 TRIB2 可以解除肝癌细胞中 C/EBPα 对 YAP/TEAD 转录激活的抑制作用。总之,我们的研究揭示了肝癌特异性 Wnt 转录输出的调控机制,并表明 TRIB2 作为信号枢纽,在癌细胞中整合了 Wnt/β-catenin、Hippo/YAP 和 C/EBPα 通路。
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