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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI159860 |
| _version_ | 1797634457078857728 |
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| author | Zi-Yan Yang Xian-Chun Yan Jia-Yu-Lin Zhang Liang Liang Chun-Chen Gao Pei-Ran Zhang Yuan Liu Jia-Xing Sun Bai Ruan Juan-Li Duan Ruo-Nan Wang Xing-Xing Feng Bo Che Tian Xiao Hua Han |
| author_facet | Zi-Yan Yang Xian-Chun Yan Jia-Yu-Lin Zhang Liang Liang Chun-Chen Gao Pei-Ran Zhang Yuan Liu Jia-Xing Sun Bai Ruan Juan-Li Duan Ruo-Nan Wang Xing-Xing Feng Bo Che Tian Xiao Hua Han |
| author_sort | Zi-Yan Yang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:08:06Z |
| format | Article |
| id | doaj.art-bd6ace602e4845dc99347c79490dd45e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:06Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-bd6ace602e4845dc99347c79490dd45e2023-11-07T16:20:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113320Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stressZi-Yan YangXian-Chun YanJia-Yu-Lin ZhangLiang LiangChun-Chen GaoPei-Ran ZhangYuan LiuJia-Xing SunBai RuanJuan-Li DuanRuo-Nan WangXing-Xing FengBo CheTian XiaoHua HanHuman 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.https://doi.org/10.1172/JCI159860Vascular biology |
| spellingShingle | Zi-Yan Yang Xian-Chun Yan Jia-Yu-Lin Zhang Liang Liang Chun-Chen Gao Pei-Ran Zhang Yuan Liu Jia-Xing Sun Bai Ruan Juan-Li Duan Ruo-Nan Wang Xing-Xing Feng Bo Che Tian Xiao Hua Han Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress The Journal of Clinical Investigation Vascular biology |
| 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 | Vascular biology |
| url | https://doi.org/10.1172/JCI159860 |
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