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Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress
Zi-Yan Yang, … , Tian Xiao, Hua Han
Zi-Yan Yang, … , Tian Xiao, Hua Han
Published August 22, 2023
Citation Information: J Clin Invest. 2023;133(20):e159860. https://doi.org/10.1172/JCI159860.
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Research Article Vascular biology Article has an altmetric score of 2

Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress

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Abstract

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.

Authors

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

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Figure 6

Endothelial Spen ablation represses tumor growth.

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Endothelial Spen ablation represses tumor growth.
(A and B) Human lung c...
(A and B) Human lung cancer biopsies were immunostained for CD31 and SPEN, and the SPEN intensity in the CD31+ area was quantified. (A) Tumor progression was analyzed between the endothelial SPEN–high and SPEN–low groups. (B) The correlation of endothelial SPEN level with overall survival was evaluated by Kaplan-Meier analysis. n = 30 patients per group. (C) Mice were inoculated with LLC cells. Tumor size was monitored, and tumor weights were compared on day 21 after inoculation (n = 10). (D and E) Control and eSpen–/– mice were inoculated with LLC cells. (D) Tumors at day 21 after inoculation were immunostained with Ki67 and quantitatively compared (n = 4). Scale bar: 100 μm. (E) Tumor hypoxia was evaluated by staining with Hypoxyprobe (n = 4). (F) Mice were inoculated with luciferase+ LLC cells. Tumors were removed on day 14 after inoculation, and the mice were maintained for an additional 28 days. Lung metastasis was evaluated using chemoluminescence (n = 4). (G) Mice were inoculated with GFP+ LLC cells. Circulating GFP+ LLC cells in blood were counted on day 21 after inoculation (n = 8 and 5 for control and eSpen–/–, respectively). The white arrowheads denote GFP+ LLC cells in blood. Scale bar: 100 μm. (H) Mice were inoculated with LLC cells. Tumors were removed on day 21 after inoculation, and mouse survival was plotted thereafter (n = 9). Data represent mean ± SEM. Log-rank (Mantel-Cox) test was used for B and H; 1-way ANOVA with Tukey’s multiple comparisons test was used for C; χ2 analyses were used for A, except for no. of metastasis positive lymph nodes; unpaired 2-tailed Student’s t test was used for D–G and no. of metastasis positive lymph nodes in A.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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