Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis

Abstract Background Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are ther...

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Autores principales:	Huan-Lei Wu, Sen-Mao Li, Yao-chen Huang, Qi-Dong Xia, Peng Zhou, Xian-Miao Li, Xiao Yu, Shao-Gang Wang, Zhang-Qun Ye, Jia Hu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	HnRNPK Prostate cancer miRNA Post-transcriptional regulation Degradation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/17632217f0ab41c58417813f77b0b4c9
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spelling	oai:doaj.org-article:17632217f0ab41c58417813f77b0b4c92021-12-05T12:23:44ZTranscriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis10.1186/s12935-021-02331-x1475-2867https://doaj.org/article/17632217f0ab41c58417813f77b0b4c92021-12-01T00:00:00Zhttps://doi.org/10.1186/s12935-021-02331-xhttps://doaj.org/toc/1475-2867Abstract Background Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. Methods qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. Results In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3’-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. Conclusion Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.Huan-Lei WuSen-Mao LiYao-chen HuangQi-Dong XiaPeng ZhouXian-Miao LiXiao YuShao-Gang WangZhang-Qun YeJia HuBMCarticleHnRNPKProstate cancermiRNAPost-transcriptional regulationDegradationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCancer Cell International, Vol 21, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HnRNPK Prostate cancer miRNA Post-transcriptional regulation Degradation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	HnRNPK Prostate cancer miRNA Post-transcriptional regulation Degradation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Huan-Lei Wu Sen-Mao Li Yao-chen Huang Qi-Dong Xia Peng Zhou Xian-Miao Li Xiao Yu Shao-Gang Wang Zhang-Qun Ye Jia Hu Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
description	Abstract Background Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. Methods qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. Results In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3’-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. Conclusion Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.
format	article
author	Huan-Lei Wu Sen-Mao Li Yao-chen Huang Qi-Dong Xia Peng Zhou Xian-Miao Li Xiao Yu Shao-Gang Wang Zhang-Qun Ye Jia Hu
author_facet	Huan-Lei Wu Sen-Mao Li Yao-chen Huang Qi-Dong Xia Peng Zhou Xian-Miao Li Xiao Yu Shao-Gang Wang Zhang-Qun Ye Jia Hu
author_sort	Huan-Lei Wu
title	Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
title_short	Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
title_full	Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
title_fullStr	Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
title_full_unstemmed	Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis
title_sort	transcriptional regulation and ubiquitination-dependent regulation of hnrnpk oncogenic function in prostate tumorigenesis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/17632217f0ab41c58417813f77b0b4c9
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Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis

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