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Targeting USP42 induces DNA damage and inhibits cell growth in prostate cancer
Yinghao Zhou1, Chenchen Chen1, Yibo Meng1
1Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
Background:
Prostate cancer (PCa) is one of the most common cancers in men worldwide. During its progression, deubiquitination-mediated alterations in biological processes play critical roles in tumor metabolism, stem cell characteristics, immune evasion, DNA damage repair, and chemoresistance. A comprehensive investigation of the deubiquitinases involved in PCa development holds significant clinical value as regards inhibiting tumor growth and overcoming drug resistance.
Methods:
Clinical databases were analyzed to identify differentially expressed deubiquitinases in PCa. Immunohistochemical analysis of PCa samples was used to evaluate USP42 expression in normal and tumor tissues. The effects of USP42 inhibition on PCa cell proliferation were assessed both in vitro and in vivo through MTT assays, colony-formation assays, and a subcutaneous xenograft tumor model in nude mice. The regulation of USP42 expression by the androgen receptor (AR) was investigated by culturing cells in low-androgen medium, modulating AR expression, and analyzing protein expression correlations through immunohistochemical staining of clinical samples and database analysis. The potential mechanisms underlying USP42-mediated effects on PCa cell proliferation were explored using RNA sequencing and data-independent acquisition proteomics. In addition, γ-H2A.X detection, MTT assays, and colony-formation assays were conducted to evaluate the impacts of USP42 inhibition on DNA damage repair and the therapeutic efficacy of olaparib in PCa cells.
Results:
Knockdown of USP42 significantly reduced PCa cell growth both in vitro and in vivo. USP42 expression was elevated in PCa tissues compared with normal tissues. Further investigation confirmed that AR positively regulated USP42 mRNA and protein expression in PCa cells. Mechanistically, USP42 inhibition induced significant defects in DNA damage repair. Moreover, USP42 knockdown markedly enhanced the tumor-suppressive effects of olaparib when used in combination.
Insights
Inhibition of USP42, a deubiquitinase, significantly reduces prostate cancer (PCa) cell growth and enhances chemotherapy efficacy. USP42 is upregulated by the androgen receptor (AR) and its inhibition impairs DNA repair in PCa.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (PCa) progression involves deubiquitination-mediated alterations impacting tumor metabolism, stemness, immune evasion, DNA repair, and chemoresistance.
- Deubiquitinases (DUBs) are critical regulators of these processes, making them potential therapeutic targets for PCa.
- Investigating DUBs in PCa is clinically significant for inhibiting tumor growth and overcoming drug resistance.
Purpose of the Study:
- To investigate the role of USP42, a deubiquitinase, in prostate cancer (PCa) development and progression.
- To explore the regulatory relationship between the androgen receptor (AR) and USP42 expression in PCa.
- To evaluate the therapeutic potential of USP42 inhibition, alone and in combination with olaparib, for PCa treatment.
Main Methods:
- Differential expression analysis of deubiquitinases in PCa clinical databases.
- Immunohistochemical evaluation of USP42 expression in normal and tumor tissues.
- In vitro and in vivo assessment of USP42 inhibition effects on PCa cell proliferation, DNA damage repair, and drug sensitivity.
Main Results:
- USP42 expression is significantly elevated in PCa tissues compared to normal tissues.
- Knockdown of USP42 markedly reduces PCa cell proliferation both in vitro and in vivo.
- Androgen receptor (AR) positively regulates USP42 expression in PCa cells.
- USP42 inhibition leads to significant DNA damage repair defects and enhances olaparib efficacy.
Conclusions:
- USP42 is a key deubiquitinase promoting prostate cancer cell growth and is regulated by the AR.
- Inhibition of USP42 impairs DNA damage repair and sensitizes PCa cells to PARP inhibitors like olaparib.
- Targeting USP42 represents a promising therapeutic strategy for prostate cancer, particularly in combination therapies.
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