Original Articles
Liangsong Zhu, Jianfeng Wang, Wen Kong, Jiwei Huang, Baijun Dong, Yiran Huang, Wei Xue, Jin Zhang. LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 324-334

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling
Liangsong Zhu, Jianfeng Wang, Wen Kong, Jiwei Huang, Baijun Dong, Yiran Huang, Wei Xue, Jin Zhang
Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
Abstract:
Histone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6% (224/358) of clear cell renal cell carcinomas (ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage (P=0.006), especially tumor stage (P=0.017) and lymph node metastasis (P=0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival (P<0.001) and recurrence-free survival (P<0.001) of ccRCC patients. We further show that LSD1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC in vitro and in vivo. Mechanistically, inhibition of LSD1 decreased the H3K4 demethylation at the CDKN1A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of LSD1 in ccRCC and suggest the therapeutic potential of LSD1 inhibitors in ccRCC treatment.
Key words:    Clear cell renal cell carcinoma    LSD1    Prognosis    Proliferation    P21   
Received: 2018-06-06     Revised: 2018-08-23
DOI: 10.1016/j.apsb.2018.10.006
Funds: This study was supported by the National Nature Science Foundation of China (21472208 and 81625022).We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Corresponding author: Wei Xue, Jin Zhang     Email:uroxuewei@163.com;med-zhangjin@vip.sina.com
Author description:
Service
PDF(KB) Free
Print
0
Authors
Liangsong Zhu
Jianfeng Wang
Wen Kong
Jiwei Huang
Baijun Dong
Yiran Huang
Wei Xue
Jin Zhang

References:
1. Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-21.
2. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma:2014 update. Eur Urol 2015;67:913-24.
3. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010;7:245-57.
4. Gerez J, Tedesco L, Bonfiglio JJ, Fuertes M, Barontini M, Silberstein S, et al. RSUME inhibits VHL and regulates its tumor suppressor function. Oncogene 2015;34:4855-66.
5. Zhao W, Qiu Y, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm Sin B 2017;7:27-37.
6. 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. Anti-Cancer Drugs 2016;27:383-97.
7. Liu LJ, Wang W, Huang SY, Hong Y, Li G, Lin S, et al. Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium (iii) metal-based compound. Chem Sci 2017;8:4756-63.
8. Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 2018;361:290-5.
9. Lainez N, Garcia-Donas J, Esteban E, Puente J, Saez MI, Gallardo E, et al. Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study. BMC cancer 2016;16:135.
10. Reu FJ, Bae SI, Cherkassky L, Leaman DW, Lindner D, Beaulieu N, et al. Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol 2006;24:3771-9.
11. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41-5.
12. Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000;406:593-9.
13. Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 2009;69:3802-9.
14. Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R, et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 2011;71:7238-49.
15. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004;119:941-53.
16. Hou H, Yu H. Structural insights into histone lysine demethylation. Curr Opin Struct Biol 2010;20:739-48.
17. Zuchegna C, Aceto F, Bertoni A, Romano A, Perillo B, Laccetti P, et al. Mechanism of retinoic acid-induced transcription:histone code, DNA oxidation and formation of chromatin loops. Nucleic Acids Res 2014;42:11040-55.
18. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and panhistone deacetylase inhibitor against human AML cells. Leukemia 2014;28:2155-64.
19. Qin Y, Zhu W, Xu W, Zhang B, Shi S, Ji S, et al. LSD1 sustains pancreatic cancer growth via maintaining HIF1α-dependent glycolytic process. Cancer Lett 2014;347:225-32.
20. Chen C, Wang Y, Wang S, Liu Y, Zhang J, Xu Y, et al. LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1. Int J Oncol 2017;50:942-52.
21. Kashyap V, Ahmad S, Nilsson EM, Helczynski L, Kenna S, Persson JL, et al. The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer. Mol Oncol 2013;7:555-66.
22. Yang C, Wang W, Liang JX, Li G, Vellaisamy K, Wong CY, et al. A rhodium (Ⅲ)-based inhibitor of lysine-specific histone demethylase 1 as an epigenetic modulator in prostate cancer cells. J Med Chem 2017;60:2597-603.
23. Baek SH, Kim KI. Regulation of HIF-1α stability by lysine methylation. BMB Rep 2016;49:245-6.
24. Hong Q, Li O, Zheng W, Xiao WZ, Zhang L, Wu D, et al. lncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma. Cell Death Dis 2017;8:e2772.
25. Wang J, Xu Y, Zhu L, Zou Y, Kong W, Dong B, et al. Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression. J Cancer Res Clin Oncol 2018;144:39-52.
26. Mizutani A, Koinuma D, Seimiya H, Miyazono K. The Arkadia-ESRP2 axis suppresses tumor progression:analyses in clear-cell renal cell carcinoma. Oncogene 2016;35:3514-23.
27. Shin G, Kang TW, Yang S, Baek SJ, Jeong YS, Kim SY. GENT:gene expression database of normal and tumor tissues. Cancer Inform 2011;10:149-57.
28. Maiques-Diaz A, Somervaille TC. LSD1:biologic roles and therapeutic targeting. Epigenomics 2016;8:1103-16.
29. Duan YC, Ma YC, Qin WP, Ding LN, Zheng YC, Zhu YL, et al. Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment. Eur J Med Chem 2017;140:392-402.
30. Deng J. How to unleash mitochondrial apoptotic blockades to kill cancers?. Acta Pharm Sin B 2017;7:18-26.
31. Shi Y, Sawada J, Sui G, Affar el B, Whetstine JR, Lan F, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 2003;422:735-8.
32. Kong L, Zhang P, Li W, Yang Y, Tian Y, Wang X, et al. KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells. Oncotarget 2016;7:27959-74.
33. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995;9:1149-63.
34. Abbas T, Dutta A. p21 in cancer:intricate networks and multiple activities. Nat Rev Cancer 2009;9:400-14.
35. Sherr CJ, Roberts JM. CDK inhibitors:positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501-12.
36. Kreis NN, Louwen F, Yuan J. Less understood issues:p21(cip1) in mitosis and its therapeutic potential. Oncogene 2015;34:1758-67.
37. Gartel AL, Radhakrishnan SK. Lost in transcription:p21 repression, mechanisms, and consequences. Cancer Res 2005;65:3980-5.
38. Liu YW, Xia R, Lu K, Xie M, Yang F, Sun M, et al. LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-mediated H3K4me2 demethylation. Mol Cancer 2017;16:39.
39. Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer 2011;128:574-86.
40. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005;437:436-9.