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ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice

Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC...

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Autores principales: Wang, Shiyan, Wong, Chi Chun, Zhang, Yanquan, Huang, Junzhe, Li, Chuangen, Zhai, Jianning, Wang, Guoping, Wei, Hong, Zhang, Xueji, He, Housheng Hansen, Yu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639438/
https://www.ncbi.nlm.nih.gov/pubmed/34615997
http://dx.doi.org/10.1038/s41388-021-01938-8
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author Wang, Shiyan
Wong, Chi Chun
Zhang, Yanquan
Huang, Junzhe
Li, Chuangen
Zhai, Jianning
Wang, Guoping
Wei, Hong
Zhang, Xueji
He, Housheng Hansen
Yu, Jun
author_facet Wang, Shiyan
Wong, Chi Chun
Zhang, Yanquan
Huang, Junzhe
Li, Chuangen
Zhai, Jianning
Wang, Guoping
Wei, Hong
Zhang, Xueji
He, Housheng Hansen
Yu, Jun
author_sort Wang, Shiyan
collection PubMed
description Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues (P < 0.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in Apc(Min/+) and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545(Δ/Δ)Apc(Min/+) mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC.
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spelling pubmed-86394382021-12-15 ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice Wang, Shiyan Wong, Chi Chun Zhang, Yanquan Huang, Junzhe Li, Chuangen Zhai, Jianning Wang, Guoping Wei, Hong Zhang, Xueji He, Housheng Hansen Yu, Jun Oncogene Article Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues (P < 0.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in Apc(Min/+) and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545(Δ/Δ)Apc(Min/+) mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC. Nature Publishing Group UK 2021-10-06 2021 /pmc/articles/PMC8639438/ /pubmed/34615997 http://dx.doi.org/10.1038/s41388-021-01938-8 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
Wang, Shiyan
Wong, Chi Chun
Zhang, Yanquan
Huang, Junzhe
Li, Chuangen
Zhai, Jianning
Wang, Guoping
Wei, Hong
Zhang, Xueji
He, Housheng Hansen
Yu, Jun
ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title_full ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title_fullStr ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title_full_unstemmed ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title_short ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
title_sort znf545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639438/
https://www.ncbi.nlm.nih.gov/pubmed/34615997
http://dx.doi.org/10.1038/s41388-021-01938-8
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