Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

Zhongrui Li; Lan Zhang; Dongrui Liu; Zhanghui Yang; Di Xuan; Yi Zhang

doi:10.1038/s41420-021-00622-w

Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

Cell Death Discov. 2022 Jan 10;8(1):14. doi: 10.1038/s41420-021-00622-w.

Authors

Zhongrui Li¹, Lan Zhang², Dongrui Liu¹, Zhanghui Yang¹, Di Xuan¹, Yi Zhang³

Affiliations

¹ Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China.
² Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China.
³ Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China. hvwilfzobscbts@163.com.

Abstract

Chemotherapy resistance of tumor cells causes failure in anti-tumor therapies. Recently, N-terminal regulator of chromatin condensation 1 methyltransferase (NRMT) is abnormally expressed in different cancers. Hence, we speculate that NRMT may pay a crucial role in the development of chemosensitivity in retinoblastoma. We characterized the upregulation of NRMT in the developed cisplatin (CDDP)-resistant retinoblastoma cell line relative to parental cells. Loss-of-function experiments demonstrated that NRMT silencing enhanced chemosensitivity of retinoblastoma cells to CDDP. Next, NRMT was identified to enrich histone-H3 lysine 4 trimethylation in the promoter of centromere protein A (CENPA) by chromatin immunoprecipitation assay. Rescue experiments suggested that CENPA reduced chemosensitivity by increasing the viability and proliferation and reducing apoptosis of CDDP-resistant retinoblastoma cells, which was reversed by NRMT. Subsequently, CENPA was witnessed to induce the transcription of Myc and to elevate the expression of B cell lymphoma-2. At last, in vivo experiments confirmed the promotive effect of NRMT knockdown on chemosensitivity of retinoblastoma cells to CDDP in tumor-bearing mice. Taken together, NRMT is an inhibitor of chemosensitivity in retinoblastoma. Those findings shed new light on NRMT-targeted therapies for retinoblastoma.