2. Academic Validation
  3. Histone acetyltransferase 1 promotes gemcitabine resistance by regulating the PVT1/EZH2 complex in pancreatic cancer

Histone acetyltransferase 1 promotes gemcitabine resistance by regulating the PVT1/EZH2 complex in pancreatic cancer

  • Cell Death Dis. 2021 Sep 25;12(10):878. doi: 10.1038/s41419-021-04118-4.
Yan Sun  # 1 2,  Dianyun Ren  # 1 2,  Yingke Zhou 1 2,  Jian Shen 3 4,  Heshui Wu 5 6,  Xin Jin 7 8
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 2 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 3 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. 1024263571@qq.com.
  • 4 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. 1024263571@qq.com.
  • 5 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. heshuiwu@hust.edu.cn.
  • 6 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. heshuiwu@hust.edu.cn.
  • 7 Department of Urology, The Second Xiangya Hospital, Central South University, 410011, Changsha, Hunan, China. jinxinxy2@csu.edu.cn.
  • 8 Uro-Oncology Institute of Central South University, 410011, Changsha, Hunan, China. jinxinxy2@csu.edu.cn.
  • # Contributed equally.
PMID: 34564701 DOI: 10.1038/s41419-021-04118-4
Abstract

The poor prognosis of pancreatic Cancer is primarily due to the development of resistance to therapies, including gemcitabine. The long noncoding RNA PVT1 (lncRNA PVT1) has been shown to interact with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), promoting gemcitabine resistance in pancreatic Cancer. In this study, we found Histone Acetyltransferase 1 (HAT1) enhanced the tolerance of pancreatic Cancer cells to gemcitabine and HAT1-mediated resistance mechanisms were regulated by PVT1 and EZH2. Our results showed that the aberrant HAT1 expression promoted gemcitabine resistance, while silencing HAT1 restored gemcitabine sensitivity. Moreover, HAT1 depletion caused a notable increase of gemcitabine sensitivity in gemcitabine-resistant pancreatic Cancer cell lines. Further research found that HAT1 increased PVT1 expression to induce gemcitabine resistance, which enhanced the binding of bromodomain containing 4 (BRD4) to the PVT1 promoter, thereby promoting PVT1 transcription. Besides, HAT1 prevented EZH2 degradation by interfering with ubiquitin protein Ligase E3 component n-recognin 4 (UBR4) binding to the N-terminal domain of EZH2, thus maintaining EZH2 protein stability to elevate the level of EZH2 protein, which also promoted HAT1-mediated gemcitabine resistance. These results suggested that HAT1 induced gemcitabine resistance of pancreatic Cancer cells through regulating PVT1/EZH2 complex. Given this, Chitosan (CS)-tripolyphosphate (TPP)-siHAT1 nanoparticles were developed to block HAT1 expression and improve the antitumor effect of gemcitabine. The results showed that CS-TPP-siHAT1 nanoparticles augmented the antitumor effects of gemcitabine in vitro and in vivo. In conclusion, HAT1-targeted therapy can improve observably gemcitabine sensitivity of pancreatic Cancer cells. HAT1 is a promising therapeutic target for pancreatic Cancer.

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