Effect of m6A methyltransferase METTL3 ‐mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer

Abstract

N6-methyladenosine (m6A) methyltransferase METTL3 has been implicated in carcinogenesis, which may be associated the overexpression of MALAT1. However, the downstream mechanics actions remain largely unknown. This study intends to probe the downstream mechanism of the N6-methyladenosine (m 6 A) methyltransferase METTL3 and MALAT1 in adriamycin resistance in breast cancer. Through Bioinformatics databases lncMAP, TCGA and GTEx, we predicted the downstream transcription factors E2F1 and AGR2 of MALAT1 in breast cancer. The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases were used to screen the downstream target genes of MALAT1. MeRIP-qPCR was used to detect the m 6 A level of MALAT1 in cells. RIP was used to detect the binding between MALAT1 and E2F1, and chromatin immunoprecipitation (ChIP) for the binding of E2F1 to AGR2 promoter. Cell Counting Kit-8 and colony formation assays were used to detect cell viability. Transwell was used to detect cell invasion. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression of related genes and proteins. A nude mouse xenograft tumor model was established to observe the effect of METTL3 on adriamycin resistance of breast cancer. The total survival of mice after exogenous gene silencing was analyzed by the Kaplan-Meier method. METTL3 was highly expressed in adriamycin-resistant breast cancer cells. METTL3 promotes adriamycin resistance in breast cancer cells. METTL3 mediates the expression of MALAT1 in adriamycinresistant breast cancer through m 6 A. MALAT1 increases adriamycin resistance in breast cancer cells by recruiting E2F1 to activate AGR2 transcription. METTL3 can regulate the expression of MALAT1 through m 6 A, mediate the E2F1/AGR2 axis, and promote the adriamycin resistance of breast cancer. METTL3 may modify MALAT1 protein through m 6 A, recruit E2F1 and activate downstream AGR2 expression, thus promoting adriamycin resistance in breast cancer.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer

“…METTL3 targeted MALAT1/miR-26b/HMGA2 axis and caused EMT and promotion of migration and invasion in breast cancer ( 50 ). METTL3 regulated MALAT1/E2F1/AGR2 pathway and subsequently controlled Adriamycin resistance in breast cancer ( 51 ). We also found that METTL3 controlled the expression of MALAT1 in pancreatic cancer cells.…”

Biological and pharmacological roles of m6A modifications in cancer drug resistance

“…The latest study revealed the potential function of METTL3 in adriamycin resistance (ADR) in BC. METTL3-mediated m 6 A regulated MALAT1 expression, thereby recruiting E2F1 and promoting AGR2 expression, which resulted in ADR in BC [ 127 ]. A recent study in GC showed that the reader IGF3BP1 recognized METTL3-mediated m6A modification on apoptotic protease-activating factor 1-binding lncRNA to maintain its stability, which inhibited GC cell apoptosis and led to multidrug resistance [ 147 ].…”

The Key Role of RNA Modification in Breast Cancer

“…METTL3 was demonstrated to upregulate PD-L1 expression via IGF2BP3 by m 6 A-dependent manner to modulate immune surveillance in breast cancer ( Wan et al, 2022 ). The high level of METTL3 induced EMT, invasion and migration by targeting MALAT1/miR-26b/HMGA2 axis ( Li et al, 2022 ). DROSHA RNase III was upregulated in a number of cancers and interacted with β-catenin to activate stanniocalcin 1 (STC1) in an RNA cleavage-independent manner, which in turn contributed to the properties of breast cancer stem-like cells (BCSCs).…”

“…S-adenosylhomocysteine (SAH) can be hydrolyzed to produce adenosine (adenine) and homocysteine, which can inhibit cellular methyltransferase activity through substrate inhibition, and regulates transmethylation through inhibition of METTL3-METTL14 activity ( Eckert et al, 2019 ). The expression of MALAT1 was shown to be enhanced by METTL3 through recruitment of E2F transcription factor 1 (E2F1), resulting in transcription of anterior gradient 2 (AGR2), and subsequent adriamycin resistance in breast cancer ( Li et al, 2022 ). In a further study, METTL3 also promoted maturation of miRNA-221-3p in an m 6 A-dependent manner, which negatively regulated HIPK2, upregulated the target gene Che-1, and induced chemoresistance of breast cancer cells to doxorubicin ( Pan et al, 2021 ).…”