Haichuan Wang1, Shanshan Zhang2, Yi Zhang2, Jiaoyuan Jia3, Jingxiao Wang4, Xianqiong Liu5, Jie Zhang6, Xinhua Song2, Silvia Ribback7, Antonio Cigliano8, Matthias Evert8, Bingyong Liang9, Hong Wu10, Diego F Calvisi11, Yong Zeng12, Xin Chen13. 1. 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. 2. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA. 3. 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. 4. 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. 5. 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. 6. 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. 7. Institute of Pathology, University of Greifswald, Greifswald, Germany. 8. Institute of Pathology, University of Regensburg, Regensburg, Germany. 9. 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. 10. 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. 11. Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de. 12. 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. Electronic address: zengyong@medmail.com.cn. 13. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA. Electronic address: xin.chen@ucsf.edu.
Abstract
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-CreERT2 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.
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-CreERT2 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.
Authors: Iván M Moya; Stéphanie A Castaldo; Laura Van den Mooter; Soheil Soheily; Leticia Sansores-Garcia; Jelle Jacobs; Inge Mannaerts; Jun Xie; Elisabeth Verboven; Hanne Hillen; Ana Algueró-Nadal; Ruchan Karaman; Matthias Van Haele; Weronika Kowalczyk; Maxime De Waegeneer; Stefaan Verhulst; Panagiotis Karras; Leen van Huffel; Lars Zender; Jean-Christophe Marine; Tania Roskams; Randy Johnson; Stein Aerts; Leo A van Grunsven; Georg Halder Journal: Science Date: 2019-11-22 Impact factor: 47.728
Authors: Matthias Van Haele; Iván M Moya; Ruçhan Karaman; Guy Rens; Janne Snoeck; Olivier Govaere; Frederik Nevens; Chris Verslype; Baki Topal; Diethard Monbaliu; Georg Halder; Tania Roskams Journal: Int J Mol Sci Date: 2019-02-01 Impact factor: 5.923
Authors: Antonio Cigliano; Shanshan Zhang; Silvia Ribback; Sara Steinmann; Marcella Sini; Cindy E Ament; Kirsten Utpatel; Xinhua Song; Jingxiao Wang; Maria G Pilo; Fabian Berger; Haichuan Wang; Junyan Tao; Xiaolei Li; Giovanni M Pes; Serena Mancarella; Gianluigi Giannelli; Frank Dombrowski; Matthias Evert; Diego F Calvisi; Xin Chen; Katja Evert Journal: J Exp Clin Cancer Res Date: 2022-06-03