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 3

Inhibition of mTOR by sunitinib represses SND1 translation via 4E-BP1.

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Inhibition of mTOR by sunitinib represses SND1 translation via 4E-BP1. (...
(A and B) Immunoblot analysis of SND1, mTOR, and its downstream target, 4E-BP1, in hiPSC-ECs treated with DMSO or sunitinib (2 μM) for 48 hours revealed a reduction in p-mTOR and p–4E-BP1 in response to sunitinib treatment. Two-tailed Student’s t test. Data are presented as mean ± SD. ***P < 0.001. n = 6 replicates from the differentiation of 2 individual hiPSC lines. (C and D) hiPSC-ECs were treated with rapamycin (100 nM) or sunitinib or pretreated with MHY-1485 (10 μM) for 12 hours before being treated with sunitinib (2 μM) or DMSO. Rapamycin treatment inhibited the SND1 level, and repression of SND1 by sunitinib was rescued by MHY-1485. One-way ANOVA. Data are presented as mean ± SD. *P < 0.05, ***P < 0.001. n = 6 replicates from the differentiation of 3 individual hiPSC lines. (E) hiPSC-ECs were transduced with lentivirus carrying a doxycycline-inducible (DOX-inducible) 4E-BP1-4Ala mutant gene. Following exposure (exp.) to DOX (1 μg/mL) for 48 hours, protein expression of SND1 and 4E-BP1 was detected by immunoblotting. (F and G) hiPSC-ECs were transduced with shScramble (shScr) or shRNAs against 4E-BP1 and 4E-BP2 (sh4E-BP1/2), before being treated with sunitinib (2 μM) or DMSO. Repression of SND1 by sunitinib was rescued when both 4E-BPs were genetically suppressed. One-way ANOVA. Data are presented as mean ± SD. **P < 0.01, ***P < 0.001. n = 9 replicates from the differentiation of 3 individual hiPSC lines. (H) hiPSC-ECs were treated with ZM 323881 (VEGFR2 inhibitor) at different concentrations for 24 hours. Immunoblot analysis indicated that ZM 323881 did not affect SND1 in ECs. (I) hiPSC-ECs were treated with CP-673451 (PDGFR inhibitor) at different concentrations for 24 hours. Immunoblot analysis indicated that CP-673451 did not affect SND1 in ECs. (J) hiPSC-ECs were treated with imatinib (c-Kit and PDGFR inhibitor) at different concentrations for 24 hours. Numerical values below the blots indicate quantification of SND1 bands relative to GAPDH. Immunoblot analysis indicated that imatinib did not affect SND1 in ECs.