Dataset Information

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc.

ABSTRACT:

Background

c-Myc, a well-established oncogene, plays an important role in the initiation and progression of various cancers, including prostate cancer. However, its mechanism in cancer cell remains largely unknown and whether there exist a deubiquitinase targeting c-Myc also remains elusive.

Methods

Bioinformatic analysis and shRNA screening methods were used to identify potential deubiquitinases that correlate with c-Myc gene signature. Cell proliferation and viability were measured by Cell-Counting-Kit 8 and colony formation assays. A mouse xenograft model of PC3 cells was established to confirm the function of USP16 in vivo. The interaction between USP16 and c-Myc protein was assessed by co-immunoprecipitation and protein co-localization assays. Immunohistochemistry staining was performed to detect the expression of USP16, Ki67, and c-Myc in xenograft tissues and clinical tumour tissues. Furthermore, the correlation between USP16 and c-Myc was confirmed by RNA sequencing.

Results

Functional analyses identified USP16, known as a deubiquitinase, was strongly correlated with the c-Myc gene signature. Depletion of USP16 was shown to significantly suppress the growth of PCa cells both in vitro and in vivo. Co-immunoprecipitation and ubiquitination assays confirmed that USP16 served as a novel deubiquitinase of c-Myc and overexpression of c-Myc significantly rescued the effects of USP16 disruption. Immunohistochemistry staining and RNA-seq tactics were further used to confirm the positive correlation between USP16 and c-Myc expression. Expression of USP16 in human PCa tissues was higher than that seen in normal prostate tissues and its high expression was found associated with poor prognosis.

Conclusions

USP16 serves as a novel deubiquitinase of c-Myc. Downregulation of USP16 markedly suppressed PCa cell growth both in vitro and in vivo. USP16 regulates PCa cell proliferation by deubiquitinating and stabilizing c-Myc, making it a potential therapeutic candidate for the treatment of PCa.

SUBMITTER: Ge J

PROVIDER: S-EPMC7866668 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc.

Ge Jianchao J Yu Wandong W Li Junhong J Ma Hangbin H Wang Pengyu P Zhou Yinghao Y Wang Yang Y Zhang Jun J Shi Guowei G

Journal of experimental & clinical cancer research : CR 20210205 1

<h4>Background</h4>c-Myc, a well-established oncogene, plays an important role in the initiation and progression of various cancers, including prostate cancer. However, its mechanism in cancer cell remains largely unknown and whether there exist a deubiquitinase targeting c-Myc also remains elusive.<h4>Methods</h4>Bioinformatic analysis and shRNA screening methods were used to identify potential deubiquitinases that correlate with c-Myc gene signature. Cell proliferation and viability were measu ...[more]

PMID: 33546726

Similar Datasets

Project description:Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.

Dataset Information

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc.

Background

Methods

Results

Conclusions

Publications

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc.

Similar Datasets

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