TAZ is indispensable for c-MYC-induced hepatocarcinogenesis,Journal of Hepatology

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TAZ is indispensable for c-MYC-induced hepatocarcinogenesis
Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-08-28 , DOI: 10.1016/j.jhep.2021.08.021
Haichuan Wang ₁ , Shanshan Zhang ₂ , Yi Zhang ₂ , Jiaoyuan Jia ₃ , Jingxiao Wang ₄ , Xianqiong Liu ₅ , Jie Zhang ₆ , Xinhua Song ₂ , Silvia Ribback ₇ , Antonio Cigliano ₈ , Matthias Evert ₈ , Bingyong Liang ₉ , Hong Wu ₁₀ , Diego F Calvisi ₈ , Yong Zeng ₁₀ , Xin Chen ₂

Affiliation

Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA; Department of Oncology and Hematology, the Second Hospital, Jilin University, Changchun, China.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA; School of Pharmacy, Hubei University of Chinese Medicine Wuhan, Hubei, China.
Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.
Institute of Pathology, University of Greifswald, Greifswald, Germany.
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA; Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Background & Aims

Mounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ to c-MYC-induced liver tumor development.

Methods

The requirement for YAP and/or TAZ in c-Myc-driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. An hepatocyte-specific inducible TTR-CreER^T2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples.

Results

We found that the Hippo cascade is inactivated in c-Myc-induced mouse HCC. Intriguingly, TAZ mRNA levels and activation status correlated with c-MYC activity in human and mouse HCC, but YAP mRNA levels did not. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc-induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc-driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc-driven HCC progression.

Conclusions

TAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of patients with HCC and c-MYC activation.

Lay summary

The identification of novel treatment targets and approaches for patients with hepatocellular carcinoma is crucial to improve survival outcomes. We identified TAZ as a transcriptional target of c-MYC which plays a critical role in c-MYC-dependent hepatocarcinogenesis. TAZ could potentially be targeted for the treatment of patients with c-MYC-driven hepatocellular carcinoma.

中文翻译：

TAZ 对于 c-MYC 诱导的肝癌发生是必不可少的

背景与目标

越来越多的证据表明，在肝细胞癌 (HCC) 中，Hippo 下游效应子 Yes 相关蛋白 (YAP) 和具有 PDZ 结合基序 (TAZ) 的转录共激活因子。我们研究了 YAP 和/或 TAZ 对 c-MYC 诱导的肝肿瘤发展的功能贡献。

方法

使用条件Yap、Taz和Yap分析了 c-Myc 驱动的肝癌发生中对 YAP 和/或 TAZ 的需求；Taz敲除 (KO) 小鼠。应用肝细胞特异性诱导型 TTR-CreER ^T2 KO 系统评估 YAP 和 TAZ 在肿瘤进展过程中的作用。在人类 HCC 样本中分析了 YAP、TAZ、c-MYC 和 BCL2L12 的表达模式。

结果

我们发现 Hippo 级联在 c-Myc 诱导的小鼠 HCC 中失活。有趣的是，TAZ mRNA 水平和激活状态与人和小鼠 HCC 中的 c-MYC 活性相关，但YAP mRNA 水平不相关。我们证明 TAZ 是 c-MYC 的直接转录靶标。在 c-Myc 诱导的小鼠 HCC 中，消融Taz而不是Yap完全阻止了肿瘤的发展。从机制上讲，需要 TAZ 来避免肿瘤发生期间 c-Myc 诱导的肝细胞凋亡。抗凋亡BCL2L12基因被鉴定为由 YAP/TAZ 特异性调节的新靶标，其沉默强烈抑制 c-Myc 驱动的小鼠肝癌发生。在 c-Myc 小鼠 HCC 病变中，条件性敲除Taz而非Yap导致肿瘤消退，支持 TAZ 对 c-Myc 驱动的 HCC 进展的要求。