The emerging roles and mechanism of N6-methyladenosine (m6A) modifications in urologic tumours progression

Abstract

Prostate cancer (PCa), bladder cancer (BC), and renal cell cancer (RCC) are the most common urologic tumours in males. N6-methyladenosine (m⁶A), adenosine N6 methylation, is the most prevalent RNA modification in mammals. Increasing evidence suggests that m⁶A plays a crucial role in cancer development. In this review, we comprehensively analyzed the influence of m⁶A methylation on Prostate cancer, bladder cancer, and renal cell cancer and the relationship between the expression of relevant regulatory factors and their development and occurrence, which provides new insights and approaches for the early clinical diagnosis and targeted therapy of urologic malignancies.

Keywords: N6-methyladenosine; coding RNAs; epitranscriptome; non-coding RNAs; posttranscriptional modification; urologic tumours.

FIGURE 1

The biology functions of m6A regulators. The three kinds of m6A enzymes are as follows: “writers” (METTL3, METTL14, WTAP, METTL16, VIRMA, ZC3H13 and RBM15), “erasers” (FTO and ALKBH5), and “readers” (YTHDF1/2/3, YTHDC1/2 and IGF2BP1/2/3). They regulate the deposition of m6A modification and affect the translation, stability (degradation and stabilization) and splicing of RNA.

FIGURE 2

In PCa, m⁶A regulatory proteins contribute to tumorigenesis and progression by interacting with various RNAs. METTL3 and WTAP stimulate the progression of PCa by promoting the expression levels of Lnc-PVT1, Lnc-MALAT1, Lnc-SNHG7, MYC, LEF1, GLI1, ITGB, KIFEC and EIF3C. In addition, miR-320d and circ-PDE5A inhibit the expression of METTL3 and WTAP, leading to PCa suppression. METTL3 and METTL14 stimulate the progression of PCa by inhibiting the expression levels of USP4, NKX3-1, LHPP and THBS1. METTL3 suppresses the progression of PCa by inhibiting the expression levels of STAT6. LXA4 inhibits the expression of METTL3, leading to PCa progression. FTO suppress the progression of PCa by affecting the expression levels of MC4R and CLIC4. YTHDF1, YTHDC2, and IGF2BPs stimulate the progression of PCa by promoting the expression of EIF3C, PLK1, IGF1R, KIF3C, LEF1 and HDAC4. YTHDF2 stimulate the progression of PCa by inhibiting the expression of USP4, LHPP, NKX3-1, MOB3b and THBS1. In addition, ELK1 and circ_0003258 promote the expression of YTHDF1 and IGF2BP3, leading to PCa progression. circ-MID1 could sponge miR-330–3p to promote YTHDC2 expression.

FIGURE 3

In BC, m⁶A regulatory proteins contribute to tumorigenesis and progression by interacting with various RNAs. METTL3 and WTAP stimulate the progression of BC by promoting the expression levels of PD-L1, BIRC5, miR-146a-5p, pri-miR221/222, TEK, VEGF-A, ITGA6, CDCP1, AFF4 and NRF2. Upstream regulators JNK and HIF1A promote the expression of METTL3, leading to BC progression. METTL3 promote the progression of BC by inhibiting the expression levels of KLF4 and SETD7. METTL14 suppresses the progression of BC by inhibiting the expression levels of Vimentin and Notch1. FTO promote the tumorigenesis and progression of BC by regulating the expression of Lnc-MALAT1, miR-576, MMP9 and PYCR1. In addition, miR-5581–3p inhibits the expression of FTO, leading to BC suppression. USP18 promotes the expression of FTO, leading to BC progression. YTHDF1, YTHDF3, IGF2BP1 and IGF2BP3 stimulate the progression of BC by promoting the expression of NRF2, CDCP1, ITGA6, PD-L1, FSCN1, MYC, BIRC5 and JAK/STAT. In addition, circ-PTPRA inhibits the expression of IGF2BP1, leading to BC suppression. YTHDF2 promote the progression of BC by inhibiting the expression levels of KLF4 and SETD7.

FIGURE 4

In RCC, m⁶A regulatory proteins contribute to tumorigenesis and progression by interacting with various RNAs. METTL3, METTL14 and WTAP stimulate the progression of RCC by promoting the expression levels of HHLA2, ABCD1, S1PR3 and CDK2. miR-501–3p inhibit the expression of WATP, leading to RCC suppression. METTL14 suppresses the progression of RCC by promoting the expression levels of Pten. METTL3 and METTL14 suppress the progression of RCC by inhibiting the expression levels of EMT, PI3K, BPTF, ITGB4, Lnc-LSG1 and Lnc-NEAT1_1. FTO and ALKBH5 stimulate/inhibit the progression of RCC by affecting the expression levels of AURKB, PDK1, SIK2, and PGC-1α. In addition,miR-155 inhibits the expression of FTO, leading to RCC suppression. IGF2BP1, IGF2BP2 and IGF2BP3 promote the tumorigenesis and progression of RCC by regulating the expression levels of S1PR3, CDK4, Lnc-DUXAP9 and Lnc-CDKN2B-AS1. Lnc-DMDRMR bounds the IGF2BP3 expression and helps stabilize the cell-cycle kinase CDK4, thereby supporting the malignancy state of RCC. YTHDF1, YTHDF2, YTHDC1 and IGF2BP2 inhibit the tumorigenesis and progression of RCC by regulating the expression levels of Pten, ITGB4, PDK1, Lnc-NEAT1_1, Lnc-LSG1, circ-POLR2A, SERPINH1 and SIK2. In addition, circ-TNPO3 interacts with IGF2BP2 to destabilize the mRNA of SERPINH1, thereby inhibiting the tumorigenesis and progression of RCC.