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Raloxifene, identified as a novel LSD1 inhibitor, suppresses the migration of renal cell carcinoma

    Yuan Ma‡

    Institute of Clinical Medicine, Urodynamic Center and Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

    ‡Authors contributed equally

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    ,
    Yan Zheng‡

    Key Laboratory of Immunology and Kidney Disease, People’s Hospital of Henan Province, Zhengzhou 450003, China

    ‡Authors contributed equally

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    ,
    Yanli Ji

    School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China

    ,
    Xiuli Wang

    *Author for correspondence:

    E-mail Address: 15038187728@163.com

    Department of Orthopaedic, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

    &
    Baoxian Ye

    *Author for correspondence:

    E-mail Address: 15038187728@163.com

    College of Chemistry, Zhengzhou University, Zhengzhou 450001, China

    Published Online:https://doi.org/10.4155/fmc-2020-0323

    Aim: As an important epigenetic modulator, histone lysine-specific demethylase 1 (LSD1) has been proved to be associated with the progression of renal cell carcinoma (RCC). Discovering novel LSD1 inhibitors offers therapeutic potential for RCC treatment. Methods & Results: We identified raloxifene as a novel LSD1 inhibitor (IC50 = 2.08 μM) through small compound library screening. Molecular docking indicated raloxifene might bind LSD1 in the flavin adenine dinucleotide (FAD) binding cavity in a reversible manner. Cell viability and migration assays showed raloxifene could suppress the proliferation and migration of RCC cells bearing overexpressed LSD1. Conclusion: Our findings indicated that LSD1 might be a promising therapeutic target for RCC and that raloxifene could serve as a lead compound for further anti-RCC metastasis drug discovery.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Ljungberg B, Campbell SC, Cho HY et al. The epidemiology of renal cell carcinoma. Eur. Urol. 60(4), 615–621 (2011).
    • 2. Ljungberg B, Bensalah K, Canfield S et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur. Urol. 67(5), 913–924 (2015).
    • 3. Motzer RJ, Jonasch E, Agarwal N et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 15(6), 804–834 (2017).
    • 4. Zhao W, Qiu Y, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm. Sinica B 7(1), 27–37 (2017).
    • 5. Takyar S, Diaz J, Sehgal M, Sapunar F, Pandha H. First-line therapy for treatment-naive patients with advanced/metastatic renal cell carcinoma: a systematic review of published randomized controlled trials. Anticancer Drugs 27(5), 383–397 (2016).
    • 6. Shi Y, Lan F, Matson C et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119(7), 941–953 (2004). •• First article to report LSD1 as a histone lysine-specific demethylase.
    • 7. Huang J, Sengupta R, Espejo AB et al. p53 is regulated by the lysine demethylase LSD1. Nature 449(7158), 105–108 (2007).
    • 8. Wang J, Hevi S, Kurash JK et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat. Genet. 41(1), 125–129 (2009).
    • 9. Ooi SKT, Qiu C, Bernstein E et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448(7154), 714–717 (2007).
    • 10. Zhao L-J, Fan Q-Q, Li Y-Y et al. LSD1 deletion represses gastric cancer migration by upregulating a novel miR-142-5p target protein CD9. Pharmacol. Res. 159, 104991 (2020). • Downregulation of LSD1 could repress the migration of gastric cancer through a novel miRNA.
    • 11. Ketscher A, Jilg CA, Willmann D et al. LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. Oncogenesis 3(10), e120–e120 (2014).
    • 12. Augert A, Eastwood E, Ibrahim AH et al. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition. Sci. Signal. 12(567), eaau2922 (2019).
    • 13. Hu X, Xiang D, Xie Y et al. LSD1 suppresses invasion, migration and metastasis of luminal breast cancer cells via activation of GATA3 and repression of TRIM37 expression. Oncogene 38(44), 7017–7034 (2019).
    • 14. Alsaqer SF, Tashkandi MM, Kartha VK et al. Inhibition of LSD1 epigenetically attenuates oral cancer growth and metastasis. Oncotarget 8(43), 73372–73386 (2017).
    • 15. Zhang J, Zhao D, Li Q et al. Upregulation of LSD1 promotes migration and invasion in gastric cancer through facilitating EMT. Cancer Manag. Res. 11, 4481–4491 (2019).
    • 16. Boulding T, McCuaig RD, Tan A et al. LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer. Sci. Rep. 8(1), 73 (2018).
    • 17. Yang G-J, Lei P-M, Wong S-Y, Ma D-L, Leung C-H. Pharmacological inhibition of LSD1 for cancer treatment. Molecules 23(12), 3194 (2018).
    • 18. Li ZR, Suo FZ, Hu B et al. Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor. Bioorg. Chem. 84, 164–169 (2019).
    • 19. Zheng YC, Shen DD, Ren M et al. Baicalin, a natural LSD1 inhibitor. Bioorg. Chem. 69, 129–131 (2016).
    • 20. Li Z-R, Suo F-Z, Guo Y-J et al. Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation. Bioorg. Chem. 97, 103648 (2020).
    • 21. Liu H-M, Suo F-Z, Li X-B et al. Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors. Eur. J. Med. Chem. 175, 357–372 (2019).
    • 22. Sareddy GR, Viswanadhapalli S, Surapaneni P, Suzuki T, Brenner A, Vadlamudi RK. Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway. Oncogene 36(17), 2423–2434 (2017).
    • 23. Hoshino I, Akutsu Y, Murakami K et al. Histone demethylase LSD1 inhibitors prevent cell growth by regulating gene expression in esophageal squamous cell carcinoma cells. Ann. Surg. Oncol. 23(1), 312–320 (2016).
    • 24. Gehling VS, McGrath JP, Duplessis M et al. Design and synthesis of styrenylcyclopropylamine LSD1 inhibitors. ACS Med. Chem. Lett. 11(6), 1213–1220 (2020).
    • 25. Chu Y, Xiao Z, Jing N et al. Arborinine, a potential LSD1 inhibitor, inhibits epithelial-mesenchymal transition of SGC-7901 cells and adriamycin-resistant gastric cancer SGC-7901/ADR cells. Invest. New Drugs doi:10.1007/s10637-020-01016-y (2020) (Epub ahead of print).
    • 26. Li Y, Sun Y, Zhou Y, Li X, Zhang H, Zhang G. Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia. J. Enzyme Inhib. Med. Chem. 36(1), 207–217 (2021).
    • 27. Romussi A, Cappa A, Vianello P et al. Discovery of reversible inhibitors of KDM1A efficacious in acute myeloid leukemia models. ACS Med. Chem. Lett. 11(5), 754–759 (2020).
    • 28. Zhu L, Wang J, Kong W et al. LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling. Acta Pharm. Sinica B 9(2), 324–334 (2019). •• LSD1 was overexpressed in 52.6% of clear cell renal cell cancer. LSD1 inhibitors could suppress the growth of clear cell renal cell carcinoma via upregulating p21 signaling.
    • 29. Wu K, Woo SM, Kwon TK. The histone lysine-specific demethylase 1 inhibitor, SP2509 exerts cytotoxic effects against renal cancer cells through downregulation of Bcl-2 and Mcl-1. J. Cancer Prev. 25(2), 79–86 (2020).
    • 30. Kumar A, Kumari N, Nallabelli N et al. Expression profile of H3K4 demethylases with their clinical and pathological correlation in patients with clear cell renal cell carcinoma. Gene 739, 144498 (2020).
    • 31. Wang Y, Liu J, Bai H, Dang Y, Lv P, Wu S. Long intergenic non-coding RNA 00152 promotes renal cell carcinoma progression by epigenetically suppressing P16 and negatively regulates miR-205. Am. J. Cancer Res. 7(2), 312–322 (2017). •• Demonstrated that LSD1 was involved in RCC progression.
    • 32. Duan YC, Guan YY, Zhai XY et al. Discovery of resveratrol derivatives as novel LSD1 inhibitors: design, synthesis and their biological evaluation. Eur. J. Med. Chem. 126, 246–258 (2017).