m⁶A-induced lncDBET promotes the malignant progression of bladder cancer through FABP5-mediated lipid metabolism

Abstract

The limited effect of adjuvant therapy for advanced bladder cancer (BCa) leads to a poor prognosis. Increasing evidence has shown that RNA N6-methyladenosine (m 6 A) modification plays important functional roles in tumorigenesis. Nevertheless, the role and mechanism of m6A-modified noncoding RNAs (ncRNAs) in BCa remain largely unknown. Methods: RT-PCR, western blotting and ONCOMINE dataset were used to determine the dominant m 6 A-related enzyme in BCa. M 6 A-lncRNA epitranscriptomic microarray was used to screen candidate targets of METTL14. RT-PCR, MeRIP and TCGA dataset were carried out to confirm the downstream target of METTL14. CHIRP/MS was conducted to identify the candidate proteins binding to lncDBET. RT-PCR, western blotting, RIP and KEGG analysis were used to confirm the target of lncDBET. The levels of METTL14, lncDBET and FABP5 were tested in vitro and in vivo . CCK-8, EdU, transwell and flow cytometry assays were performed to determine the oncogenic function of METTL14, lncDBET and FABP5, and their regulatory networks. Results : We identified that the m 6 A level of total RNA was elevated and that METTL14 was the dominant m6A-related enzyme in BCa. m 6 A modification mediated by METTL14 promoted the malignant progression of BCa by promoting the expression of lncDBET. Upregulated lncDBET activated the PPAR signalling pathway to promote the lipid metabolism of cancer cells through direct interaction with FABP5, thus promoting the malignant progression of BCa in vitro and in vivo . Conclusions : Our study establishes METTL14/lncDBET/FABP5 as a critical oncogenic axis in BCa.

Critical roles and clinical perspectives of RNA methylation in cancer

“…415 In bladder cancer, METTL14 induces lncDBET overexpression, and along with FA binding protein 5 (FABP5), it promotes lipid metabolism and the malignant progression of bladder cancer. 416 In GBM, constitutively activated EGFR/SRC/ERK pathway results in YTHDF2 overexpression and subsequently downregulate LXRA and HIVEP2 expression, thereby disrupting cholesterol homeostasis and sustaining GBM tumorigenesis. 417 The m 5 C modification was recently found to regulate diverse biological processes involved in lipid metabolism.…”

“…In CC, depleted levels of the demethylase ALKBH5 indicate an unfavorable prognosis, and ALKBH5 functionally suppresses the expression of silent mating type information regulation 2 homologue 3 and ACC1 in an IGF2BP1‐dependent manner, ultimately inhibiting FA synthesis 415 . In bladder cancer, METTL14 induces lncDBET overexpression, and along with FA binding protein 5 (FABP5), it promotes lipid metabolism and the malignant progression of bladder cancer 416 . In GBM, constitutively activated EGFR/SRC/ERK pathway results in YTHDF2 overexpression and subsequently downregulate LXRA and HIVEP2 expression, thereby disrupting cholesterol homeostasis and sustaining GBM tumorigenesis 417 …”

LncRNAs‐circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

“…[136] On the other hand, m6A modified lncDBET in bladder cancer (BCa) and lncRNA CCAT1 in LUAD can both interact with FABP5 directly to activate the PPAR signaling pathway or PPAR-RXR transcriptional complex in order to promote lipogenesis, proliferation and migration of cancers. [137,138] Additionally, circ_ZFR in breast cancer (BC) and circPUM1 in clear cell renal cell carcinoma (ccRCC) can both ab-sorb miRNAs (miR-223-3p and miR-340-5p, respectively) to regulate FABP7-mediated proliferation and progression of these cancer cells. [139,140] FAO or 𝛽-oxidation in mitochondria and peroxisome is the major pathway for degradation of fatty acids and production of ATP and NADPH, with CPT1 being one of the most important regulatory targets.…”

“…[ 171 ] Additionally, m6A‐induced lncDBET has been identified to promote the proliferation and migration of bladder cancer by modulating the FABP5/PPAR signaling pathway‐mediated lipid metabolism. [ 137 ] Another lncRNA TINCR was found to be significantly upregulated in nasopharyngeal carcinoma, where TINCR promoted de novo lipogenesis, proliferation, and metastasis of nasopharyngeal carcinoma via ACLY‐PADI1‐MAPK‐MMP2/9 pathway. [ 103 ]…”

m6A-immune-related lncRNA prognostic signature for predicting immune landscape and prognosis of bladder cancer

“…Lnc-LBCS was found inhibit self-renewal, chemoresistance, and tumor initiation of bladder cancer stem cells through epigenetic silencing of SOX2 both in vitro and in vivo [ 14 ]. m6A-induced lncDBET was reported to promote the malignant progression of bladder cancer through FABP5-mediated lipid metabolism in vitro and in vivo [ 15 ]. Moreover, increasing research has used lncRNAs as biomarker in predicting response in bladder cancer treatment, including ferroptosis-related, m6A-related, and immune-related lncRNA models [ 16 – 18 ].…”