2. Academic Validation
  3. E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1

E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1

  • Clin Epigenetics. 2023 May 5;15(1):77. doi: 10.1186/s13148-023-01492-y.
Nannan Zhang # 1 2,  Xiaoliang Gao # 1,  Qiangqiang Yuan # 1,  Xin Fu # 3,  Pengliang Wang 2,  Fenglin Cai 2,  Hui Liu 4,  Jing Zhang 4,  Han Liang 2,  Yongzhan Nie 5,  Jingyu Deng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
  • 2 Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
  • 3 Guangxi Medical University, Nanning, 530021, Guangxi, China.
  • 4 College of Life Sciences, Northwest University, Xi'an, 710069, China.
  • 5 State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China. yongznie@fmmu.edu.cn.
  • 6 Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. dengery@126.com.
  • # Contributed equally.
PMID: 37147733 DOI: 10.1186/s13148-023-01492-y
Abstract

Background: Downregulation of certain tumor-suppressor genes (TSGs) by aberrant methylation of CpG islands in the promoter region contributes a great deal to the oncogenesis and progression of several cancers, including gastric Cancer (GC). Protocadherin 10 (PCDH10) is a newly identified TSG in various cancers and is downregulated in GC; however, the specific mechanisms of PCDH10 in GC remain elusive. Here, we elucidated a novel epigenetic regulatory signaling pathway involving the E3 ubiquitin Ligase RNF180 and DNA Methyltransferase 1 (DNMT1), responsible for modulating PCDH10 expression by affecting its promoter methylation.

Results: We revealed that PCDH10 was downregulated in GC cells and tissues, and low PCDH10 expression was correlated with lymph node metastasis and poor prognosis in patients with GC. Additionally, PCDH10 overexpression suppressed GC cell proliferation and metastasis. Mechanistically, DNMT1-mediated promoter hypermethylation resulted in decreased expression of PCDH10 in GC tissues and cells. Further analysis revealed that RNF180 can bind directly to DNMT1 and was involved in DNMT1 degradation via ubiquitination. Additionally, a positive correlation was found between RNF180 and PCDH10 expression and an inverse association between DNMT1 and PCDH10 expression showed considerable prognostic significance.

Conclusion: Our data showed that RNF180 overexpression upregulated PCDH10 expression via ubiquitin-dependent degradation of DNMT1, thus suppressing GC cell proliferation, indicating that the RNF180/DNMT1/PCDH10 axis could be a potential therapeutic target for GC treatment.

Keywords

DNA methylation; DNMT1; Gastric cancer; PCDH10; RNF180; Tumor suppressor; Ubiquitination.

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