Translational regulation of SND1 governs endothelial homeostasis during stress
Zhenbo Han, … , Soroush Tahmasebi, Sang-Ging Ong
Zhenbo Han, … , Soroush Tahmasebi, Sang-Ging Ong
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e168730. https://doi.org/10.1172/JCI168730.
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Research Article Vascular biology

Translational regulation of SND1 governs endothelial homeostasis during stress

Abstract

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell–derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain–containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.

Authors

Zhenbo Han, Gege Yan, Jordan Jousma, Sarath Babu Nukala, Mehdi Amiri, Stephen Kiniry, Negar Tabatabaei, Youjeong Kwon, Sen Zhang, Jalees Rehman, Sandra Pinho, Sang-Bing Ong, Pavel V. Baranov, Soroush Tahmasebi, Sang-Ging Ong

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Figure 1

Generation of sunitinib-induced endothelial dysfunction model using hiPSCs.

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Generation of sunitinib-induced endothelial dysfunction model using hiPS...
(A) Schematic representation of the hiPSC-to-EC (iPSC-EC) differentiation workflow. (B) hiPSC-ECs were treated with various concentrations of sunitinib for 48 hours. Cell viability was determined using the PrestoBlue cell viability reagent. One-way ANOVA. Data are presented as mean ± SD. ***P < 0.001; ns, not significant. n = 12 replicates from the differentiation of 3 individual hiPSC lines. (C and D) hiPSC-ECs were treated with 2 μM sunitinib for 48 hours. EC function was determined by tube-formation assay. n = 9 replicates from the differentiation of 3 individual hiPSC lines. Scale bar: 220 μm. Two-tailed Student’s t test. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. (E and F) Representative images and quantification of wound-healing ability of hiPSC-ECs in response to treatment with DMSO or sunitinib (2 μM) for 16 hours. The yellow lines indicate the edges of the scratch wound. The scratched areas were quantified as a percentage relative to the initial area at 0 hours. n = 9 replicates from the differentiation of 3 individual hiPSC lines. Scale bars: 220 μm. Two-tailed Student’s t test. Data are presented as mean ± SD. ***P < 0.001. (G and H) Representative images of immunostaining of the DNA damage marker γ-H2AX (red) in hiPSC-ECs after sunitinib treatment (2 μM) for 48 hours. Cells were counterstained with CD31 (green), an EC marker. n = 9 replicates from the differentiation of 3 individual hiPSC lines. Scale bars: 20 and 10 μm. Two-tailed Student’s t test. Data are presented as mean ± SD. ***P < 0.001.