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Theranostics 2021; 11(11):5387-5403. doi:10.7150/thno.42345 This issue Cite

Research Paper

PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma

Jianfeng Wang1#, Chen Wang2,3#, Pan Xu2,3#, Xiao Li2,3, Yongning Lu4, Di Jin1, Xiaomao Yin1, Hao Jiang2,3, Jing Huang2,3, Huan Xiong5,6, Fei Ye7, Jia Jin7, Yu Chen2,3, Yiqian Xie8, Zhifeng Chen2, Hong Ding2, Hao Zhang2, Rongfeng Liu9, Hualiang Jiang2, Kaixian Chen2, Zhiyi Yao10, Cheng Luo2,3✉, Yiran Huang1✉, Yuanyuan Zhang2✉, Jin Zhang1✉

1. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
2. Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
3. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
4. Zhongshan hospital Fudan University, 180 Fenglin road, Shanghai 200032, China.
5. Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China.
6. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
7. College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310023, China.
8. PerkinElmer Management (Shanghai) Co. Ltd, 1670 Zhangheng Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
9. In vitro Biology, Shanghai ChemPartner Life Science Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
10. College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 210032, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Jin Zhang, E-mail: med-zhangjinsina.com; Phone: +8613661734864; Fax numbers: 02158709251. Yuanyuan Zhang, E-mail: zhangyyac.cn; Phone: +8615802158425; Fax numbers: 02150807188. Yiran Huang, E-mail: huangyiran More

Citation:
Wang J, Wang C, Xu P, Li X, Lu Y, Jin D, Yin X, Jiang H, Huang J, Xiong H, Ye F, Jin J, Chen Y, Xie Y, Chen Z, Ding H, Zhang H, Liu R, Jiang H, Chen K, Yao Z, Luo C, Huang Y, Zhang Y, Zhang J. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics 2021; 11(11):5387-5403. doi:10.7150/thno.42345. https://www.thno.org/v11p5387.htm
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Abstract

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Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear.

Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models.

Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling.

Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.

Keywords: clear cell renal cell carcinoma, protein arginine methyltransferase 1, therapeutic, lipocalin2 (LCN2), sunitinib

Citation styles

APA
Wang, J., Wang, C., Xu, P., Li, X., Lu, Y., Jin, D., Yin, X., Jiang, H., Huang, J., Xiong, H., Ye, F., Jin, J., Chen, Y., Xie, Y., Chen, Z., Ding, H., Zhang, H., Liu, R., Jiang, H., Chen, K., Yao, Z., Luo, C., Huang, Y., Zhang, Y., Zhang, J. (2021). PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics, 11(11), 5387-5403. https://doi.org/10.7150/thno.42345.

ACS
Wang, J.; Wang, C.; Xu, P.; Li, X.; Lu, Y.; Jin, D.; Yin, X.; Jiang, H.; Huang, J.; Xiong, H.; Ye, F.; Jin, J.; Chen, Y.; Xie, Y.; Chen, Z.; Ding, H.; Zhang, H.; Liu, R.; Jiang, H.; Chen, K.; Yao, Z.; Luo, C.; Huang, Y.; Zhang, Y.; Zhang, J. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics 2021, 11 (11), 5387-5403. DOI: 10.7150/thno.42345.

NLM
Wang J, Wang C, Xu P, Li X, Lu Y, Jin D, Yin X, Jiang H, Huang J, Xiong H, Ye F, Jin J, Chen Y, Xie Y, Chen Z, Ding H, Zhang H, Liu R, Jiang H, Chen K, Yao Z, Luo C, Huang Y, Zhang Y, Zhang J. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics 2021; 11(11):5387-5403. doi:10.7150/thno.42345. https://www.thno.org/v11p5387.htm

CSE
Wang J, Wang C, Xu P, Li X, Lu Y, Jin D, Yin X, Jiang H, Huang J, Xiong H, Ye F, Jin J, Chen Y, Xie Y, Chen Z, Ding H, Zhang H, Liu R, Jiang H, Chen K, Yao Z, Luo C, Huang Y, Zhang Y, Zhang J. 2021. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics. 11(11):5387-5403.

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