2. Academic Validation
  3. A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma

A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma

  • Cell Death Differ. 2022 Jul 29. doi: 10.1038/s41418-022-01040-w.
Chunle Zhao  # 1 2,  Jun Gong  # 1 2,  Yu Bai 1 2,  Taoyuan Yin 1 2,  Min Zhou 1 2,  Shutao Pan 1 2,  Yuhui Liu 1 2,  Yang Gao 1 2,  Zhenxiong Zhang 1 2,  Yongkang Shi 1 2,  Feng Zhu 1 2,  Hang Zhang 3 4,  Min Wang 5 6,  Renyi Qin 7 8
Affiliations

Affiliations

  • 1 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China.
  • 2 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China.
  • 3 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. zhanghang@hust.edu.cn.
  • 4 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. zhanghang@hust.edu.cn.
  • 5 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. wangmin0013128@aliyun.com.
  • 6 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. wangmin0013128@aliyun.com.
  • 7 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. ryqin@tjh.tjmu.edu.cn.
  • 8 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. ryqin@tjh.tjmu.edu.cn.
  • # Contributed equally.
PMID: 35906484 DOI: 10.1038/s41418-022-01040-w
Abstract

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased Deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted Cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.

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