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Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activa...

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Autores principales: Han, Jing, Chen, Xin, Xu, Jiawei, Chu, Laili, Li, Rongqing, Sun, Na, Jiang, Zhen, Liu, Hongyang, Ge, Xing, Zheng, Junnian, Yang, Jing, Ikezoe, Takayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436113/
https://www.ncbi.nlm.nih.gov/pubmed/34522170
http://dx.doi.org/10.7150/ijms.61969
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author Han, Jing
Chen, Xin
Xu, Jiawei
Chu, Laili
Li, Rongqing
Sun, Na
Jiang, Zhen
Liu, Hongyang
Ge, Xing
Zheng, Junnian
Yang, Jing
Ikezoe, Takayuki
author_facet Han, Jing
Chen, Xin
Xu, Jiawei
Chu, Laili
Li, Rongqing
Sun, Na
Jiang, Zhen
Liu, Hongyang
Ge, Xing
Zheng, Junnian
Yang, Jing
Ikezoe, Takayuki
author_sort Han, Jing
collection PubMed
description Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.
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spelling pubmed-84361132021-09-13 Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1 Han, Jing Chen, Xin Xu, Jiawei Chu, Laili Li, Rongqing Sun, Na Jiang, Zhen Liu, Hongyang Ge, Xing Zheng, Junnian Yang, Jing Ikezoe, Takayuki Int J Med Sci Research Paper Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC. Ivyspring International Publisher 2021-08-05 /pmc/articles/PMC8436113/ /pubmed/34522170 http://dx.doi.org/10.7150/ijms.61969 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Han, Jing
Chen, Xin
Xu, Jiawei
Chu, Laili
Li, Rongqing
Sun, Na
Jiang, Zhen
Liu, Hongyang
Ge, Xing
Zheng, Junnian
Yang, Jing
Ikezoe, Takayuki
Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title_full Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title_fullStr Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title_full_unstemmed Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title_short Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1
title_sort simultaneous silencing aurora-a and uhrf1 inhibits colorectal cancer cell growth through regulating expression of dnmt1 and stat1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436113/
https://www.ncbi.nlm.nih.gov/pubmed/34522170
http://dx.doi.org/10.7150/ijms.61969
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