Int J Biol Sci 2021; 17(12):3024-3035. doi:10.7150/ijbs.61117 This issue

Research Paper

UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185

Zhikun Zheng1,*, Bin Zhang2,*, Haixin Yu2, Shoukang Li1, Naicheng Song1, Xin Jin3,✉, Jinsong Li1,✉

1. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
2. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
3. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
*These authors contributed equally.

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Citation:
Zheng Z, Zhang B, Yu H, Li S, Song N, Jin X, Li J. UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185. Int J Biol Sci 2021; 17(12):3024-3035. doi:10.7150/ijbs.61117. Available from https://www.ijbs.com/v17p3024.htm

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Abstract

Graphic abstract

Background: Esophageal cancer is the sixth-most common fatal malignant tumor worldwide. Little is known regarding the genetic drivers that influence targeted therapy outcomes in patients with esophageal cancer. Exploring the pathogenesis of this lethal tumor could provide clues for developing appropriate therapeutic drugs. Ubiquitin-protein ligase E3A (UBE3A) reportedly promotes or suppresses various types of malignant tumors. However, the cancer-related role of UBE3A in esophageal cancer remains unclear.

Methods: The relationship of UBE3A with the clinicopathological features of pancreatic tumors was bioinformatically investigated in the TCGA dataset. The protein levels of UBE3A and ZNF185 were assessed by Western blot and immunohistochemistry. The role of UBE3A and ZNF185 in esophageal cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between UBE3A and ZNF185 was investigated by co-immunoprecipitation. The relationship between UBE3A, ZNF185, and NOTCH signaling pathway was explored by Western blot and quantitative real-time PCR.

Results: We found that UBE3A was upregulated in patients with esophageal cancer and enhanced the cellular progression of esophageal cancer. Moreover, we found that UBE3A degraded ZNF185 in esophageal cancer. Additionally, ZNF185 suppressed the progression of esophageal cancer by inactivating the NOTCH pathway.

Conclusions: These data demonstrated that aberrant expression of UBE3A led to enhanced progression of esophageal cancer through the ZNF185/NOTCH signaling axis. Therefore, UBE3A might be an ideal therapeutic candidate for esophageal cancer.

Keywords: UBE3A, ZNF185, NOTCH pathway, esophageal cancer