2. Academic Validation
  3. Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis

Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis

  • J Exp Clin Cancer Res. 2023 Sep 4;42(1):228. doi: 10.1186/s13046-023-02781-3.
Zhitao Han # 1 2,  Qi Jia # 3,  Jing Zhang # 3,  Miaomiao Chen 4,  Lining Wang 1,  Kai Tong 2,  Weiwei He 2,  Yajie Zhang 5 6,  Weina Zhu 5 6,  Ju Qin 5,  Tao Wang 7,  Tielong Liu 3,  Yong Ma 8,  Yuanming Chen 9,  Siluo Zha 10,  Chunlei Zhang 11 12
Affiliations

Affiliations

  • 1 School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 2 Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 3 Department of Orthopaedic Oncology, Shanghai Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, China.
  • 4 Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 5 Central Laboratory, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 6 Department of Biobank, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 7 Department of Orthopedics, Second Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 8 School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. zhongyi-my@263.net.
  • 9 Department of Orthopedics, Second Affiliated Hospital of Guangxi Medical University, 166 East Daxue Road, Nanning, 530000, Guangxi, China. rkyygk@163.com.
  • 10 Department of General Surgery, Shanghai Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. 164091006@qq.com.
  • 11 Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. chunleizh@126.com.
  • 12 Department of Orthopedics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, 157 Daming Road, Nanjing, 210023, China. chunleizh@126.com.
  • # Contributed equally.
PMID: 37667382 DOI: 10.1186/s13046-023-02781-3
Abstract

Background: Accumulating evidence has demonstrated that aberrant expression of deubiquitinating Enzymes is associated with the initiation and progression of Triple-negative breast Cancer (TNBC). The publicly available TCGA database of breast Cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast Cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events.

Methods: We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets.

Results: It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast Cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors.

Conclusion: Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC.

Keywords

CDK1; Ovarian tumor deubiquitinase; Triple-negative breast cancer (TNBC); Ubiquitylation regulation; YOD1.

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