Cargando…

Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes

BACKGROUND: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer. METHODS: Public cancer databases were analyzed to...

Descripción completa

Detalles Bibliográficos
Autores principales: Lu, Wenbao, Zhou, Meicen, Wang, Bing, Liu, Xueting, Li, Bingwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686734/
https://www.ncbi.nlm.nih.gov/pubmed/33228782
http://dx.doi.org/10.1186/s13046-020-01766-w
_version_ 1783613390777745408
author Lu, Wenbao
Zhou, Meicen
Wang, Bing
Liu, Xueting
Li, Bingwei
author_facet Lu, Wenbao
Zhou, Meicen
Wang, Bing
Liu, Xueting
Li, Bingwei
author_sort Lu, Wenbao
collection PubMed
description BACKGROUND: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer. METHODS: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1. RESULTS: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem–loop structure in the 3′ untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs. CONCLUSIONS: Our findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might be a potential molecular target for breast cancer treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-020-01766-w.
format Online
Article
Text
id pubmed-7686734
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-76867342020-11-25 Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes Lu, Wenbao Zhou, Meicen Wang, Bing Liu, Xueting Li, Bingwei J Exp Clin Cancer Res Research BACKGROUND: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer. METHODS: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1. RESULTS: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem–loop structure in the 3′ untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs. CONCLUSIONS: Our findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might be a potential molecular target for breast cancer treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-020-01766-w. BioMed Central 2020-11-23 /pmc/articles/PMC7686734/ /pubmed/33228782 http://dx.doi.org/10.1186/s13046-020-01766-w Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Lu, Wenbao
Zhou, Meicen
Wang, Bing
Liu, Xueting
Li, Bingwei
Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title_full Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title_fullStr Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title_full_unstemmed Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title_short Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
title_sort roquin1 inhibits the proliferation of breast cancer cells by inducing g1/s cell cycle arrest via selectively destabilizing the mrnas of cell cycle–promoting genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686734/
https://www.ncbi.nlm.nih.gov/pubmed/33228782
http://dx.doi.org/10.1186/s13046-020-01766-w
work_keys_str_mv AT luwenbao roquin1inhibitstheproliferationofbreastcancercellsbyinducingg1scellcyclearrestviaselectivelydestabilizingthemrnasofcellcyclepromotinggenes
AT zhoumeicen roquin1inhibitstheproliferationofbreastcancercellsbyinducingg1scellcyclearrestviaselectivelydestabilizingthemrnasofcellcyclepromotinggenes
AT wangbing roquin1inhibitstheproliferationofbreastcancercellsbyinducingg1scellcyclearrestviaselectivelydestabilizingthemrnasofcellcyclepromotinggenes
AT liuxueting roquin1inhibitstheproliferationofbreastcancercellsbyinducingg1scellcyclearrestviaselectivelydestabilizingthemrnasofcellcyclepromotinggenes
AT libingwei roquin1inhibitstheproliferationofbreastcancercellsbyinducingg1scellcyclearrestviaselectivelydestabilizingthemrnasofcellcyclepromotinggenes