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C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer

BACKGROUND: Triple‐negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integrat...

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Autores principales: Liao, Li, Deng, Ling, Zhang, Yin‐Ling, Yang, Shao‐Ying, Andriani, Lisa, Hu, Shu‐Yuan, Zhang, Fang‐Lin, Shao, Zhi‐Min, Li, Da‐Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679971/
https://www.ncbi.nlm.nih.gov/pubmed/38009308
http://dx.doi.org/10.1002/ctm2.1480
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author Liao, Li
Deng, Ling
Zhang, Yin‐Ling
Yang, Shao‐Ying
Andriani, Lisa
Hu, Shu‐Yuan
Zhang, Fang‐Lin
Shao, Zhi‐Min
Li, Da‐Qiang
author_facet Liao, Li
Deng, Ling
Zhang, Yin‐Ling
Yang, Shao‐Ying
Andriani, Lisa
Hu, Shu‐Yuan
Zhang, Fang‐Lin
Shao, Zhi‐Min
Li, Da‐Qiang
author_sort Liao, Li
collection PubMed
description BACKGROUND: Triple‐negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA‐Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. METHODS: In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real‐time quantitative polymerase chain reaction (RT‐qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142‐regulated mouse double minute 2 (MDM2)‐binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assays. RESULTS: In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up‐regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142‐mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. CONCLUSIONS: Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment.
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spelling pubmed-106799712023-11-27 C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer Liao, Li Deng, Ling Zhang, Yin‐Ling Yang, Shao‐Ying Andriani, Lisa Hu, Shu‐Yuan Zhang, Fang‐Lin Shao, Zhi‐Min Li, Da‐Qiang Clin Transl Med Research Articles BACKGROUND: Triple‐negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA‐Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. METHODS: In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real‐time quantitative polymerase chain reaction (RT‐qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142‐regulated mouse double minute 2 (MDM2)‐binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assays. RESULTS: In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up‐regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142‐mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. CONCLUSIONS: Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment. John Wiley and Sons Inc. 2023-11-27 /pmc/articles/PMC10679971/ /pubmed/38009308 http://dx.doi.org/10.1002/ctm2.1480 Text en © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Liao, Li
Deng, Ling
Zhang, Yin‐Ling
Yang, Shao‐Ying
Andriani, Lisa
Hu, Shu‐Yuan
Zhang, Fang‐Lin
Shao, Zhi‐Min
Li, Da‐Qiang
C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title_full C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title_fullStr C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title_full_unstemmed C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title_short C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer
title_sort c9orf142 transcriptionally activates mtbp to drive progression and resistance to cdk4/6 inhibitor in triple‐negative breast cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679971/
https://www.ncbi.nlm.nih.gov/pubmed/38009308
http://dx.doi.org/10.1002/ctm2.1480
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