N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating DNA repair

Siyi Jiang; Lili Gao; Jian Li; Fangrong Zhang; Yanan Zhang; Jing Liu

doi:10.3389/fcell.2024.1383232

N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating DNA repair

Front Cell Dev Biol. 2024 Mar 22:12:1383232. doi: 10.3389/fcell.2024.1383232. eCollection 2024.

Authors

Siyi Jiang¹, Lili Gao², Jian Li³, Fangrong Zhang¹, Yanan Zhang¹, Jing Liu¹

Affiliations

¹ Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, China.
² Jinan Hospital of Integrated Chinese and Western Medicine, Jinan, China.
³ Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, China.

Abstract

Studies have shown that bortezomib resistance in multiple myeloma (MM) is mediated by the abnormalities of various molecules and microenvironments. Exploring these resistance mechanisms will improve the therapeutic efficacy of bortezomib. In this study, bone marrow tissues from three patients with MM, both sensitive and resistant to bortezomib, were collected for circRNA high-throughput sequencing analysis. The relationship between circ_0000337, miR-98-5p, and target gene DNA2 was analyzed by luciferase detection and verified by RT-qPCR. We first found that circ_0000337 was significantly upregulated in bortezomib-resistant MM tissues and cells, and overexpression of circ_0000337 could promote bortezomib resistance in MM cells. circ_0000337 may act as a miR-98-5p sponge to upregulate DNA2 expression, regulate DNA damage repair, and induce bortezomib resistance. Furthermore, it was determined that the increased circ_0000337 level in bortezomib-resistant cells was due to an increased N6-methyladenosine (m6A) level, resulting in enhanced RNA stability. In conclusion, the m6A level of circ_0000337 and its regulation may be a new and potential therapeutic target for overcoming bortezomib resistance in MM.

Keywords: DNA2; M6A; bortezomib resistance; circ_0000337; multiple myeloma.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Fundamental Research Funds for the Central Universities of Central South University (Grant No. 2022ZZTS0831).