Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
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
_version_ 1785120972559351808
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
work_keys_str_mv AT yangziyan repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT yanxianchun repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT zhangjiayulin repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT liangliang repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT gaochunchen repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT zhangpeiran repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT liuyuan repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT sunjiaxing repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT ruanbai repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT duanjuanli repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT wangruonan repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT fengxingxing repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT chebo repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT xiaotian repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress
AT hanhua repressionofrrnagenetranscriptionbyendothelialspendeficiencynormalizestumorvasculaturevianucleolarstress