SPOP suppresses testicular germ cell tumors progression through ubiquitination and degradation of DPPA2

Jian Wang; Hui Zhuang; Hui Zhang; Qian Li; Xinyi Cao; Zihan Lin; Ting Lin; Xiwei Chen; Xiaoqi Ni; Jianye Yang; Yiting Zhao; Liliang Shen; Haibiao Wang; Jie Zhu; Meng Ye; Xiaofeng Jin

doi:10.1016/j.bbrc.2021.04.002

SPOP suppresses testicular germ cell tumors progression through ubiquitination and degradation of DPPA2

Biochem Biophys Res Commun. 2021 Jun 11:557:55-61. doi: 10.1016/j.bbrc.2021.04.002. Epub 2021 Apr 13.

Authors

Jian Wang¹, Hui Zhuang¹, Hui Zhang¹, Qian Li¹, Xinyi Cao¹, Zihan Lin¹, Ting Lin¹, Xiwei Chen¹, Xiaoqi Ni¹, Jianye Yang¹, Yiting Zhao¹, Liliang Shen², Haibiao Wang³, Jie Zhu³, Meng Ye¹, Xiaofeng Jin⁴

Affiliations

¹ The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China.
² Department of Urology, Yinzhou Renmin Hospital Affiliated to Medical School of Ningbo University, Ningbo, 315040, China.
³ Department of Hepato-biliary-pancreatic Surgery, The Affiliated Ningbo Medical Center of LiHuiLi Hospital of Medical School of Ningbo University, Ningbo, 315048, China.
⁴ The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China. Electronic address: jinxiaofeng@nbu.edu.cn.

PMID: 33862460
DOI: 10.1016/j.bbrc.2021.04.002

Abstract

Dysregulation of the ubiquitin-proteasome pathway is strongly associated with cancer initiation and progression. Speckle-type POZ(pox virus and zinc finger protein) protein(SPOP) is an adapter protein of CUL3-based E3 ubiquitin ligase complexes. Gene expression profiling from the Cancer Genome Atlas (TCGA) suggests that SPOP is downregulated in testicular germ cell tumors (TGCTs), but the specific contribution of this protein remains to be explored. In this study, we show that the germ line-specific factor DPPA2 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin-ligase complex. SPOP specifically binds to a SPOP-binding consensus (SBC) degron located in DPPA2 and targets DPPA2 for degradation via the ubiquitin-proteasome pathway. SPOP downregulation increases the expression of pluripotency markers OCT4 and Nanog but decreases that of early differentiation marker gene Fst. This effect is partly dependent on its activity toward DPPA2. In addition, the dysregulation of SPOP-DPPA2 axis contributes to the malignant transformation phenotypes of TGCT cells.

Keywords: DPPA2; Degradation; SPOP; TGCT; Ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / metabolism
Cell Line, Tumor
Cell Proliferation
Heterografts
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms, Germ Cell and Embryonal / genetics
Neoplasms, Germ Cell and Embryonal / metabolism*
Neoplasms, Germ Cell and Embryonal / pathology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Proteolysis
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Testicular Neoplasms / genetics
Testicular Neoplasms / metabolism*
Testicular Neoplasms / pathology
Transcription Factors / metabolism*
Ubiquitination*

Substances

Biomarkers, Tumor
DPPA2 protein, human
Nuclear Proteins
Repressor Proteins
SPOP protein, human
Transcription Factors

Supplementary concepts

Testicular Germ Cell Tumor