Cargando…
A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer
Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; h...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263627/ https://www.ncbi.nlm.nih.gov/pubmed/34234118 http://dx.doi.org/10.1038/s41419-021-03969-1 |
_version_ | 1783719425389625344 |
---|---|
author | Liu, Qian Guo, Lijuan Qi, Hongyan Lou, Meng Wang, Rui Hai, Boning Xu, Kailun Zhu, Lijun Ding, Yongfeng Li, Chen Xie, Lingdan Shen, Jing Xiang, Xueping Shao, Jimin |
author_facet | Liu, Qian Guo, Lijuan Qi, Hongyan Lou, Meng Wang, Rui Hai, Boning Xu, Kailun Zhu, Lijun Ding, Yongfeng Li, Chen Xie, Lingdan Shen, Jing Xiang, Xueping Shao, Jimin |
author_sort | Liu, Qian |
collection | PubMed |
description | Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment. |
format | Online Article Text |
id | pubmed-8263627 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82636272021-07-23 A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer Liu, Qian Guo, Lijuan Qi, Hongyan Lou, Meng Wang, Rui Hai, Boning Xu, Kailun Zhu, Lijun Ding, Yongfeng Li, Chen Xie, Lingdan Shen, Jing Xiang, Xueping Shao, Jimin Cell Death Dis Article Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment. Nature Publishing Group UK 2021-07-07 /pmc/articles/PMC8263627/ /pubmed/34234118 http://dx.doi.org/10.1038/s41419-021-03969-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Qian Guo, Lijuan Qi, Hongyan Lou, Meng Wang, Rui Hai, Boning Xu, Kailun Zhu, Lijun Ding, Yongfeng Li, Chen Xie, Lingdan Shen, Jing Xiang, Xueping Shao, Jimin A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title | A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title_full | A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title_fullStr | A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title_full_unstemmed | A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title_short | A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer |
title_sort | mybl2 complex for rrm2 transactivation and the synthetic effect of mybl2 knockdown with wee1 inhibition against colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263627/ https://www.ncbi.nlm.nih.gov/pubmed/34234118 http://dx.doi.org/10.1038/s41419-021-03969-1 |
work_keys_str_mv | AT liuqian amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT guolijuan amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT qihongyan amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT loumeng amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT wangrui amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT haiboning amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xukailun amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT zhulijun amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT dingyongfeng amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT lichen amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xielingdan amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT shenjing amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xiangxueping amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT shaojimin amybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT liuqian mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT guolijuan mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT qihongyan mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT loumeng mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT wangrui mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT haiboning mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xukailun mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT zhulijun mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT dingyongfeng mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT lichen mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xielingdan mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT shenjing mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT xiangxueping mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer AT shaojimin mybl2complexforrrm2transactivationandthesyntheticeffectofmybl2knockdownwithwee1inhibitionagainstcolorectalcancer |