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Translating Ribosome Affinity Purification TRAP for RNA Isolation from Endothelial Cells In Vivo
08:53

Translating Ribosome Affinity Purification TRAP for RNA Isolation from Endothelial Cells In Vivo

Published on: May 25, 2019

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

Zi-Yan Yang, Xian-Chun Yan, Jia-Yu-Lin Zhang

    The Journal of Clinical Investigation
    |August 22, 2023
    PubMed

    Insights

    Split end (SPEN), a transcription repressor, is crucial for blood vessel formation in tumors. Inhibiting SPEN normalizes tumor vasculature, repressing cancer growth and metastasis, offering a new therapeutic target.

    Area of Science:

    • Molecular Biology
    • Cancer Biology
    • Vascular Biology

    Background:

    • Human cancers develop chaotic, dysfunctional tumor vasculature, hindering therapeutic efficacy.
    • Mechanisms driving tumor vasculature dysfunction remain largely unknown.

    Purpose of the Study:

    • To elucidate the role of split end (SPEN) in endothelial cells (ECs) and its impact on angiogenesis.
    • To investigate SPEN's role in tumor vascularization and identify potential therapeutic targets.

    Main Methods:

    • Investigated SPEN's function in ECs using knockdown and knockout models.
    • Analyzed the effects of SPEN deficiency on angiogenesis, p53 activation, and rRNA synthesis.
    • Examined SPEN expression in human cancer biopsies and its correlation with patient survival.
    • Utilized RNA polymerase I (RNPI) inhibitor CX-5461 and cisplatin in mouse cancer models.

    Main Results:

    • SPEN deficiency in ECs attenuated proliferation and angiogenesis, linked to p53 activation via noncoding promoter RNA (pRNA).
    • Low endothelial SPEN levels in human cancers correlated with improved overall survival.
    • Endothelial SPEN deficiency repressed tumor growth and metastasis in mice by normalizing tumor vessels, dependent on p53.
    • RNPI inhibition with CX-5461 mimicked SPEN ablation effects, and combination therapy with cisplatin enhanced anti-tumor efficacy.

    Conclusions:

    • SPEN is essential for angiogenesis by regulating rRNA gene transcription and ribosomal biogenesis.
    • Targeting RNPI offers a promising strategy for tumor vessel normalization therapy in cancer treatment.
    Keywords:
    Cell stressEndothelial cellsVascular Biology

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