scholarly journals FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
Maomao Guo ◽  
Weiwan Wang ◽  
Weican Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers. Methods We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity. Results FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion. Conclusions Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

scholarly journals FOXM1  modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
Maomao Guo ◽  
Weiwan Wang ◽  
Weican Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.Methods: We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using the ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.Conclusions: Our findings indicate highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

scholarly journals FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
Maomao Guo ◽  
Weiwan Wang ◽  
Weican Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.Methods: We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.Conclusions: Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

scholarly journals FOXM1  modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
weiwan wang ◽  
Weican Zhang ◽  
zhibin xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Apoptosis ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background：Resistance to docetaxel is an important factor which affects the prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), participating in cell cycle progress and cell proliferation, has been reported to affect the sensitivity of chemotherapy. The present study aims to explore the role of FOXM1 in docetaxel resistance of PCa and how FOXM1 is associated with kinesin family member 20 A (KIF20A), which has been demonstrated to promote the development of therapeutic resistance in some cancers. Methods: We monitored cell growth by MTT and colony formation assays , and cell apoptosis and cell cycle through flow cytometry. Wound-healing and transwell assays were performed to detect cell migration and invasion. The mRNA and protein expression of gene were analyzed by by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. We determined the binding of FOXM1 on the KIF20A promoter by the ChIP assay. Tumorigenicity in nude mice was employed to assess tumorigenicity in vivo. Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, and suppressed cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). The opposite trend was found in their parental cells with exogenous FOXM1 overexpression. Furthermore, thiostrepton, a specific inhibitor for FOXM1, significantly attenuated docetaxel resistance in vitro and in vivo. Additionally, we found that FOXM1 and KIF20A were consistently overexpressed and highly correlated in PCa cells and tissues. Further studies demonstrated that FOXM1 regulated the expression of KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Moreover, KIF20A overexpression could partially reverse the effects of FOXM1 depletion on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP). Conclusions: our findings suggest that highly expressed FOXM1 may promote docetaxel resistance partly through the induction of KIF20A expression and provide insights into novel chemotherapeutic strategies for docetaxel resistance in PCa.

scholarly journals FOXM1  modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
weiwan wang ◽  
zhibin xu ◽  
gangyi zhu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Apoptosis ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background：Resistance to docetaxel is an important factor which affects the prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), participating in cell cycle progress and cell proliferation, has been reported to affect the sensitivity of chemotherapy. The present study aims to explore the role of FOXM1 in docetaxel resistance of PCa and how FOXM1 is associated with kinesin family member 20 A (KIF20A), which has been demonstrated to promote the development of therapeutic resistance in some cancers.Methods: We monitored cell growth by MTT and colony formation assays and cell apoptosis and cell cycle through flow cytometry. Wound-healing and transwell assays were performed to detect cell migration and invasion. Gene expression was analyzedby quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. We determined the binding of FOXM1 on the KIF20A promoter by the ChIP assay. Tumorigenicity in nude mice was employed to assess tumorigenicity in vivo.Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest while hampered cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). The opposite trend was found in their parental cells with exogenous FOXM1 overexpression. Furthermore, thiostrepton, a specific inhibitor for FOXM1, significantly attenuated docetaxel resistance in vitro and in vivo. Additionally, we found that FOXM1 and KIF20A were consistently overexpressed and highly correlated in PCa cells and tissues. Further studies demonstrated that FOXM1 regulated the expression of KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Moreover, KIF20A overexpression could partially reverse the effects of FOXM1 depletion on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (Bcl-2 and PARP).Conclusions: our findings suggest that FOXM1 may promote docetaxel resistance partly through the induction of KIF20A expression and provide insights into novel chemotherapeutic strategies for docetaxel resistance in PCa.

scholarly journals Circ_0084582 Facilitates Cell Growth, Migration, Invasion, and Angiopoiesis in Osteosarcoma via Mediating the miR-485-3p/JAG1 Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Gao ◽  
Xincheng Zhao ◽  
Keying Yu ◽  
Ziqiang Zhu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Protein Detection ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Reaction Cell ◽  
Cycle Progression

Osteosarcoma (OS) is the most representative bone cancer, and circular RNAs serve as pivotal regulators in the progression of OS. This research was designed to explore the role and functional mechanism of circ_0084582 in OS. Circ_0084582, microRNA-485-3p (miR-485-3p), and Jagged1 (JAG1) levels were measured by quantitative real-time polymerase chain reaction. Cell proliferation was examined via 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Cell cycle progression was analyzed by flow cytometry. Wound healing and transwell assays were performed for evaluating cell migration and invasion. Angiopoiesis was assessed using the tube formation assay. Protein detection was conducted using Western blot. The target relation was identified by the dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay. A xenograft experiment was applied for analyzing the effect of circ_0084582 on OS in vivo. Circ_0084582 was highly expressed in OS tissues and cells. Circ_0084582 knockdown reduced cell proliferation, cell cycle progression, migration, invasion, and angiopoiesis of OS cells. JAG1 was upregulated in OS, and its overexpression reversed the effects of circ_0084582 knockdown on OS cells. Circ_0084582 targeted miR-485-3p, and miR-485-3p targeted JAG1, and circ_0084582 could affect the JAG1 level by sponging miR-485-3p. The function of circ_0084582 in OS progression was also achieved by sponging miR-485-3p. Circ_0084582 knockdown decreased OS growth in vivo partly by the miR-485-3p–mediated JAG1 downregulation. These results indicate that circ_0084582 functions as a tumorigenic factor in OS via the regulation of miR-485-3p/JAG1 axis.

scholarly journals Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features 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 induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant 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 assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways 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 breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through 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 was 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 as a potential molecular target for breast cancer treatment.

scholarly journals Fstl1 Promotes Glioma Growth Through the BMP4/Smad1/5/8 Signaling Pathway

2017 ◽  
Vol 44 (4) ◽  
pp. 1616-1628 ◽  
Author(s):  
Xin Jin ◽  
Er Nie ◽  
Xu Zhou ◽  
Ailiang Zeng ◽  
Tianfu Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Cell Cycle Progression ◽  
Malignant Gliomas ◽  
Treatment Strategies ◽  
Cycle Progression ◽  
Glioma Growth

Background: Gliomas result in the highest morbidity and mortality rates of intracranial primary central nervous system tumors because of their aggressive growth characteristics and high postoperative recurrence. They are characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior in patients. Proliferation is a key aspect of the clinical progression of malignant gliomas, complicating complete surgical resection and enabling tumor regrowth and further proliferation of the surviving tumor cells. Methods: The expression of Fstl1 was detected by western blotting and qRT-PCR. We used cell proliferation and colony formation assays to measure proliferation. Then, flow cytometry was used to analyze cell cycle progression. The expression of Fstl1, p-Smad1/5/8 and p21 in GBM tissue sections was evaluated using immunohistochemical staining. Furthermore, we used coimmunoprecipitation (Co-IP) and immunoprecipitation to validate the relationship between Fstl1, BMP4 and BMPR2. Finally, we used orthotopic xenograft studies to measure the growth of tumors in vivo. Results: We found that follistatin-like 1 (Fstl1) was upregulated in high-grade glioma specimens and that its levels correlated with poor prognosis. Fstl1 upregulation increased cell proliferation, colony formation and cell cycle progression, while its knockdown inhibited these processes. Moreover, Fstl1 interacted with bone morphogenetic protein (BMP) 4, but not BMP receptor (BMPR) 2, and competitively inhibited their association. Furthermore, Fstl1 overexpression suppressed the activation of the BMP4/Smad1/5/8 signaling pathway, while BMP4 overexpression reversed this effect. Conclusion: Our study demonstrated that Fstl1 promoted glioma growth through the BMP4/Smad1/5/8 signaling pathway, and these findings suggest potential new glioblastoma treatment strategies.

The Cold-Shock Domain Protein YB-1 Is Important for Cellular Proliferation and the Prevention of Premature Senescence.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2571-2571
Author(s):  
Zhi Hong Lu ◽  
Jason T. Books ◽  
Timothy James Ley
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Cellular Proliferation ◽  
Cold Shock ◽  
Premature Senescence ◽  
Cycle Progression

Abstract Mammalian proteins containing “cold-shock” domains belong to the most evolutionarily conserved family of nucleic acid-binding proteins known in bacteria, plants, and animals. One of these proteins, YB-1, has been implicated in basic cellular functions such as cell proliferation and responses to environmental stresses. In mammalian cells, YB-1 has been shown to shuttle between the nuclear and cytoplasmic compartments. Within the nucleus, YB-1 interacts with several DNA-and pre-mRNA-binding proteins, and has been implicated in nuclear activities, including transcriptional regulation, chromatin remodeling, and pre-mRNA splicing. YB-1 is also abundant in the cytoplasm, where it binds nonspecifically to mRNA, and may act as a general regulator of mRNA stability, cytoplasmic localization, and translation. Thus, YB-1 has been proposed to function as a multifunctional regulator for the control of gene expression in both the nucleus and cytoplasm. YB-1 overexpression has been frequently detected in a variety of human cancers, often associated with unfavorable clinical outcomes. However, it remains unclear whether YB-1 overexpression contributes directly to the malignant phenotype, or whether it is simply a non-causal “marker” associated with rapid cell growth (and poor prognostic outcomes). To further assess the role of this protein in health and disease, we created mice deficient for YB-1. Complete loss of function of this gene results in fully-penetrant late embryonic and perinatal lethality. Morphological and histological analyses revealed that YB-1−/− embryos displayed major developmental and functional defects, including neurological abnormalities, hemorrhage, and respiratory failure, which probably contributed to lethality. Growth retardation occurred in all late-stage embryos, and was the result of hypoplasia in multiple organ systems. Consistent with these in vivo results, fibroblasts isolated from YB-1−/− embryos (MEFs) grew slowly and entered senescence prematurely in vitro; these defects were rescued by ectopic expression of a GFP-tagged human YB-1 cDNA. This data suggests that YB-1 plays an important cell-autonomous role in cell proliferation and prevention of premature senescence. We further showed that loss of YB-1 in early passage MEFs resulted a delay in G0/G1 to S-phase progression, and a defect in a transcriptional mechanism that normally represses the expression of the G1-specific CDK inhibitor gene p16Ink4a, and the p53 target genes p21Cip1 and Mdm2. However, YB-1 does not cause “global” changes in the transcriptome, the proteome, or protein synthesis efficiency. As predicted, p16Ink4a and p21Cip1 double knockdown by siRNA treatment led to an increase in the rate of cell proliferation, and an extension of proliferative capacity during late passages in YB-1−/− cells. Furthermore, YB-1 deficiency reduced the ability of MEFs to proliferate normally in response to c-Myc overexpression. In conclusion, our data has revealed that YB-1 is required for normal mouse development and survival, and that it plays an important role in supporting rapid cellular proliferation both in vivo and in vitro. Our data further suggests that YB-1 is a cell cycle progression regulator that is important for preventing the early onset of senescence in cultured MEF cells. This data raises the possibility that disregulated expression of YB-1 may contribute to malignant phenotypes by supporting rapid cell cycle progression, and by protecting cells from cytotoxic stresses.

scholarly journals 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

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract 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.

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