N⁶-methyladenosine (m⁶A)-mediated lncRNA DLGAP1-AS1enhances breast canceradriamycin resistance through miR-299-3p/WTAP feedback loop

Abstract

Chemotherapy resistance is identified as an obstacle for breast cancer (BC) therapy, and, besides, increasing evidence indicates that long-noncoding RNAs (lncRNAs) participate in the regulation of BC adriamycin (ADR) resistance. Here, our work shows that lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) is up-regulated in ADR-resistant BC cells (MCF-7/ADR). Clinically, higher DLGAP1-AS1 expression was closely correlated to poorer clinical prognosis. Results showed that DLGAP1-AS1 promoted the ADR IC 50 and proliferation of ADR-resistant cells. Moreover, N 6 -methyladenosine (m 6 A) methyltransferase WT1 associated protein (WTAP) binds to the m 6 A modified site of DLGAP1-AS1 and motivates its stability. Mechanistically, DLGAP1-AS1 sponged miR-299-3p through 3ʹ-untranslated region (3ʹ-UTR) binding, which in turn relieved the repression of WTAP and thus upregulated WTAP expression. In conclusion, above findings conclude that lncRNA DLGAP1-AS1 promotes BC ADR-resistance through WTAP/DLGAP1-AS1/miR-299-3p feedback loop.

N6-methyladenine- induced LINC00667 promoted breast cancer progression through m6A/KIAA1429 positive feedback loop

“…LncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) is an up-regulated mA-related lncRNA that is overexpressed in adriamycin-resistant BC cells. M 6 A methyltransferase binds to the m 6 A-modified site of DLGAP1-AS1 and motivates its stability through WTAP/DLGAP1-AS1/miR-299-3p feedback loop [ 19 ]. Thus, it can be seen that m 6 A-related lncRNA participates in tumorigenesis.…”

Role of WTAP in Cancer: From Mechanisms to the Therapeutic Potential

“…Interestingly, WTAP promotes the stability of lncRNA DLGAP1-AS1 through m 6 A modification, and lncRNA DLGAP1-AS1 upregulates WTAP expression in breast cancer through 3′-UTR binding to miR-299-3p. However, whether lncRNA DLGAP1-AS1 competes with WTAP to bind miR-299-3p remains to be understood [ 78 ].…”

“…Interestingly, overexpression of lncRNA DLGAP1-AS1 3′-UTR targeted miR-299-3p to upregulate WTAP expression. However, further exploration is required to understand the lncRNA DLGAP1-AS1/miR-299-3p/WTAP regulatory axis in breast cancer [ 78 ].…”

The Key Role of RNA Modification in Breast Cancer

“…STM2457 is an orally bioavailable small molecule METTL3 inhibitor that are slated for human clinical trials by targeting a novel mechanism for the treatment of acute myeloid leukemia and other solid and hematological cancers ( Yankova et al, 2021 ). In addition, WTAP binds to the m 6 A modified site of lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) to sponge miR-299-3p, resulting in adriamycin resistance in breast cancer ( Huang T. et al, 2021 ). The inhibitor of 2-oxoglutarate oxygenase (OG) oxidase, IOX1, significantly inhibited ALKBH5 activity.…”