1. Academic Validation
  2. Vorinostat targets UBE2C to reverse epithelial-mesenchymal transition and control cervical cancer growth through the ubiquitination pathway

Vorinostat targets UBE2C to reverse epithelial-mesenchymal transition and control cervical cancer growth through the ubiquitination pathway

  • Eur J Pharmacol. 2021 Oct 5;908:174399. doi: 10.1016/j.ejphar.2021.174399.
Botao Pan 1 Shuanghong Yin 2 Fang Peng 3 Chang Liu 1 Huiyi Liang 1 Jiyan Su 1 W L Wendy Hsiao 4 Yantao Cai 5 Dixian Luo 6 Chenglai Xia 7
Affiliations

Affiliations

  • 1 Foshan Maternal and Child Health Research Institute, South Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, 528000, China.
  • 2 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Guangdong Second Provincial General Hospital, Guangzhou, 510317, China.
  • 4 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Macau, 999078, China.
  • 5 Foshan Maternal and Child Health Research Institute, South Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, 528000, China. Electronic address: luodixian_2@163.com.
  • 6 Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Guangdong, 518000, China. Electronic address: cypeach1030@163.com.
  • 7 Foshan Maternal and Child Health Research Institute, South Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, 528000, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: xiachenglai@126.com.
Abstract

Vorinostat is a histone deacetylase inhibitor (HDACi) that was demonstrated in our previous study to inhibit the proliferation, migration, and invasion of cervical Cancer cells by regulating the PI3K/Akt signaling pathway. However, the molecular mechanism of vorinostat in cervical Cancer treatment remains to be further elucidated. A nude mouse xenograft model was established to analyze the antitumor effect of vorinostat in vivo. The combination of iTRAQ-based proteomics and parallel reaction monitoring (PRM) technology has proven to be an efficient and reliable method to identify potential targets for Cancer chemotherapy. In this study, 254 differentially expressed proteins in vorinostat-treated cervical Cancer cells, among which 180 were upregulated and 74 were downregulated, were identified by using an iTRAQ-based proteomic strategy. Subsequent bioinformatic and PRM analysis of these differentially expressed proteins indicated that UBE2C is a promising target of vorinostat in the inhibition of cervical Cancer cell proliferation. We confirmed that the expression of endogenous UBE2C in cervical Cancer cell lines was significantly higher than that in normal cervical epithelial cell lines. Additionally, we found that vorinostat downregulated the expression of UBE2C, SQSTM1/p62, N-Cadherin, vimentin and upregulated E-cadherin in SiHa and HeLa cells. Our results also showed that vorinostat can downregulate the expression of SQSTM1/p62, N-Cadherin, and vimentin during the treatment of cervical Cancer cells by regulating UBE2C, while upregulating the expression of E-cadherin. In conclusion, vorinostat reverses epithelial-mesenchymal transition by targeting UBE2C and controls the proliferation of cervical Cancer cells through the ubiquitination pathway. UBE2C can be used as a promising target for the development of vorinostat treatment strategies.

Keywords

Cervical cancer; Epithelial-mesenchymal transition; UBE2C; Ubiquitination; Vorinostat; iTRAQ-based proteomics.

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