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Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress
Human cancers induce a chaotic, dysfunctional vasculature that promotes tumor growth and blunts most current therapies; however, the mechanisms underlying the induction of a dysfunctional vasculature have been unclear. Here, we show that split end (SPEN), a transcription repressor, coordinates rRNA...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575731/ https://www.ncbi.nlm.nih.gov/pubmed/37607001 http://dx.doi.org/10.1172/JCI159860 |
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author | Yang, Zi-Yan Yan, Xian-Chun Zhang, Jia-Yu-Lin Liang, Liang Gao, Chun-Chen Zhang, Pei-Ran Liu, Yuan Sun, Jia-Xing Ruan, Bai Duan, Juan-Li Wang, Ruo-Nan Feng, Xing-Xing Che, Bo Xiao, Tian Han, Hua |
author_facet | Yang, Zi-Yan Yan, Xian-Chun Zhang, Jia-Yu-Lin Liang, Liang Gao, Chun-Chen Zhang, Pei-Ran Liu, Yuan Sun, Jia-Xing Ruan, Bai Duan, Juan-Li Wang, Ruo-Nan Feng, Xing-Xing Che, Bo Xiao, Tian Han, Hua |
author_sort | Yang, Zi-Yan |
collection | PubMed |
description | Human cancers induce a chaotic, dysfunctional vasculature that promotes tumor growth and blunts most current therapies; however, the mechanisms underlying the induction of a dysfunctional vasculature have been unclear. Here, we show that split end (SPEN), a transcription repressor, coordinates rRNA synthesis in endothelial cells (ECs) and is required for physiological and tumor angiogenesis. SPEN deficiency attenuated EC proliferation and blunted retinal angiogenesis, which was attributed to p53 activation. Furthermore, SPEN knockdown activated p53 by upregulating noncoding promoter RNA (pRNA), which represses rRNA transcription and triggers p53-mediated nucleolar stress. In human cancer biopsies, a low endothelial SPEN level correlated with extended overall survival. In mice, endothelial SPEN deficiency compromised rRNA expression and repressed tumor growth and metastasis by normalizing tumor vessels, and this was abrogated by p53 haploinsufficiency. rRNA gene transcription is driven by RNA polymerase I (RNPI). We found that CX-5461, an RNPI inhibitor, recapitulated the effect of Spen ablation on tumor vessel normalization and combining CX-5461 with cisplatin substantially improved the efficacy of treating tumors in mice. Together, these results demonstrate that SPEN is required for angiogenesis by repressing pRNA to enable rRNA gene transcription and ribosomal biogenesis and that RNPI represents a target for tumor vessel normalization therapy of cancer. |
format | Online Article Text |
id | pubmed-10575731 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-105757312023-10-16 Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress Yang, Zi-Yan Yan, Xian-Chun Zhang, Jia-Yu-Lin Liang, Liang Gao, Chun-Chen Zhang, Pei-Ran Liu, Yuan Sun, Jia-Xing Ruan, Bai Duan, Juan-Li Wang, Ruo-Nan Feng, Xing-Xing Che, Bo Xiao, Tian Han, Hua J Clin Invest Research Article Human cancers induce a chaotic, dysfunctional vasculature that promotes tumor growth and blunts most current therapies; however, the mechanisms underlying the induction of a dysfunctional vasculature have been unclear. Here, we show that split end (SPEN), a transcription repressor, coordinates rRNA synthesis in endothelial cells (ECs) and is required for physiological and tumor angiogenesis. SPEN deficiency attenuated EC proliferation and blunted retinal angiogenesis, which was attributed to p53 activation. Furthermore, SPEN knockdown activated p53 by upregulating noncoding promoter RNA (pRNA), which represses rRNA transcription and triggers p53-mediated nucleolar stress. In human cancer biopsies, a low endothelial SPEN level correlated with extended overall survival. In mice, endothelial SPEN deficiency compromised rRNA expression and repressed tumor growth and metastasis by normalizing tumor vessels, and this was abrogated by p53 haploinsufficiency. rRNA gene transcription is driven by RNA polymerase I (RNPI). We found that CX-5461, an RNPI inhibitor, recapitulated the effect of Spen ablation on tumor vessel normalization and combining CX-5461 with cisplatin substantially improved the efficacy of treating tumors in mice. Together, these results demonstrate that SPEN is required for angiogenesis by repressing pRNA to enable rRNA gene transcription and ribosomal biogenesis and that RNPI represents a target for tumor vessel normalization therapy of cancer. American Society for Clinical Investigation 2023-10-16 /pmc/articles/PMC10575731/ /pubmed/37607001 http://dx.doi.org/10.1172/JCI159860 Text en © 2023 Yang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Yang, Zi-Yan Yan, Xian-Chun Zhang, Jia-Yu-Lin Liang, Liang Gao, Chun-Chen Zhang, Pei-Ran Liu, Yuan Sun, Jia-Xing Ruan, Bai Duan, Juan-Li Wang, Ruo-Nan Feng, Xing-Xing Che, Bo Xiao, Tian Han, Hua Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title | Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title_full | Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title_fullStr | Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title_full_unstemmed | Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title_short | Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress |
title_sort | repression of rrna gene transcription by endothelial spen deficiency normalizes tumor vasculature via nucleolar stress |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575731/ https://www.ncbi.nlm.nih.gov/pubmed/37607001 http://dx.doi.org/10.1172/JCI159860 |
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