Table 2 Epigenetic modification of m6A Regulator proteins in tumorigenesis
From: Epigenetic modification of m6A regulator proteins in cancer
Modification | m6A Regulator | Cancer | Involved mechanism | Ref |
|---|---|---|---|---|
Ubiquitination | FTO | CRC | GSK3β mediated ubiquitination of demethylase FTO to reduce FTO expression. GSK3β suppresses the progression of CRC through FTO-regulated MZF1/c-Myc axis | [87] |
Ubiquitination | FTO | CRC | Downregulated FTO protein levels was correlated with a high recurrence rate and poor prognosis. Hypoxia restrained FTO protein expression through E3 ligase STRAP-meditaed degradation. FTO exerted a tumor suppressive role by inhibiting MTA1 expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by IGF2BP2, which then stabilized its mRNA | [88] |
Ubiquitination | FTO | Bladder cancer | USP18 up-regulates FTO protein, which decreased m6A level in PYCR1 thereby stabilizing PYCR1 transcript to promote bladder cancer initiation and progression | [89] |
Ubiquitination | ALKBH5 | GBM | USP36 stabilize and regulate ALKBH5. The depletion of USP36 drastically decreased the in vivo tumor growth and impaired cell proliferation, deteriorated the self-renewal of GSCs and sensitized GSCs to temozolomide (TMZ) treatment | [90] |
Ubiquitination | IGF2BP1 | HCC | FBXO45 promoted IGF2BP1 ubiquitination and subsequent activation, leading to the upregulation of PLK1 expression and liver tumorigenesis | [91] |
Ubiquitination | IGF2BP3 | GBC | TEAD4 transcriptionally activated LncRNA MNX1-AS1 suppresses IGF2BP3 degradation by recruiting USP16. MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway and subsequently activates TEAD4. MNX1-AS1 facilitates tumorigenesis, progression and metastasis of GBC through a MNX1-AS1/IGF2BP3/Hippo pathway positive feedback loop | [92] |
Ubiquitination | IGF2BP3 | CRC | Upregulated USP11 protected IGF2BP3 from degradation via deubiquitination thereby promoting tumorigenesis in CRC | [93] |
Ubiquitination | HNRNPA2B1 | Pancreatic cancer | Upregulated Linc01232 by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway promoted the migration and invasion of PC cells | [94] |
Ubiquitination | KIAA1429 | CRC | Upregulated USP29 mediated deubiquitination to stabilize the protein levels of KIAA1429, thereby promoting the stability of SOX8 mRNA through m6A modification to facilitate the malignant proliferation | [95] |
Ubiquitination | METTL14 | Bladder cancer | METTL14 overexpression inhibits BCa cell malignancy through USP38. METTL14 stabilizes USP38 mRNA by inducing m6A modification and enhances USP38 mRNA stability in YTHDF2-dependent manner. USP38 mediates the deubiquitination of METTL14 protein | [96] |
Ubiquitination | METTL3 | Breast cancer | PIN1 interacted with METTL3 and prevented its ubiquitin-dependent proteasomal and lysosomal degradation, thereby increasing the m6A modification of TAZ and EGFR mRNA, resulting in their efficient translation, eventually promoting tumorigenesis in breast cancer | [97] |
SUMOylation | METTL3 | HCC | SUMOylation of METTL3 by SUMO1 was increased high metastatic potential and progression via controlling Snail mRNA homeostasis in an m6A methyltransferase activity-dependent manner | [98] |
SUMOylation | METTL3 | CRC | METTL3, circ_0000677, and ABCC1 were upregulated in CRC. SUMOylation of METTL3 facilitates CRC progression by promoting circ_0000677 in an m6A-dependent manner, thereby upregulating ABCC1 expression | [99] |
SUMOylation | METTL3 | NSCLC | SUMOylation of METTL3 by SUMO1 promotes tumorigenesis. SUMOylation of METTL3, which can be reduced by an SUMO1-specific protease SENP1, significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs | [100] |
SUMOylation | FTO | HCC | SIRT1 exerts an oncogenic role by down-regulating FTO through RANBP2-mediated FTO SUMOylation and degradation | [101] |
SUMOylation | HNRNPA2B1 | Breast cancer | PIAS2-mediated SUMOylated HNRNPA2B1 associates with replication protein A1 (RPA1). HNRNPA2B1 expression may function as an independent predictor of good prognosis. HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors | [102] |
SUMOylation | HNRNPA2B1 | Glioblastoma | Hypoxia promotes the transfer of hnRNP A2/B1 to the cytoplasm by upregulating SUMOylation of hnRNP A2/B1 to eliminate miR-204-3p. Exosomal miR-204-3p promoted tube formation of vascular endothelial cells through the ATXN1/STAT3 pathway. The SUMOylation inhibitor TAK-981 can inhibit the exosome-sorting process of miR-204-3p to inhibit tumor growth and angiogenesis | [103] |
SUMOylation | IGF2BP2 | Glioma | SUMOylation of IGF2BP2 by SUMO1 increased IGF2BP2 protein expression through blocking its ubiquitin-proteasome pathway-dependant degradation. Up-regulated IGF2BP2 enhances the stability of OIP5-AS1, thereby increasing the binding of OIP5-AS1 to miR-495-3p, weakening the binding of miR-495-3p to the 3’UTR of HIF1A and MMP14 mRNA, and ultimately promoting the formation of VM in glioma | [104] |
SUMOylation | YTHDF2 | NSCLC | SUMOylation of YTHDF2 increases its binding affinity of m6A-modified mRNAs leading to cancer progression | [105] |
Acetylation | RBM15 | ccRCC | Histone 3 acetylation modification by EP300/CBP upregulated RBM15 and promotes ccRCC progression. RBM15 enhanced the stability of CXCL11 mRNA in an m6A-dependent manner and promote macrophage infiltration and M2 polarization by promoting the secretion of CXCL11 | [106] |
Acetylation | METTL3 | ESCC | Upregulated METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. KAT2A mediated H3K27 acetylation transcriptionly activate METTL3, whereas SIRT2 exerted the opposite effects. Elvitegravir suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation | [107] |
Acetylation | METTL3 | Breast cancer | Acetylation of METTL3 by EP300/CBP disrupts migration and invasion potential of breast cancer cells | [108] |
Acetylation | METTL3 | HCC | METTL3 acetylation mediated reduced N6-Methyladenosine to promotes MTF1 expression and cancer progression | [109] |
Lactylation | METTL3 | CRC | Lactylation of METTL3 by acetyltransferase p300 induce Mettl3 expression through H3K18la. The lactylation METTL3-JAK1-STAT3 regulatory axis potently induces the immunosuppressive functions of tumor-infiltrating myeloid cells to promote tumor immune escape | [110] |
Lactylation | YTHDF2 | Ocular melanoma | Lactylation of YTHDF2 by EP300 at H3K18la. YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma | [111] |
O-GlcNAcylation | YTHDF2 | HCC | O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 promote its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized MCM2 and MCM5 transcripts in an m6A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. OGT inhibitor OSMI-1 significantly suppressed HCC progression through targeting YTHDF2 O-GlcNAcylation | [112] |
Methylation | RBM15 | Leukemia | RBM15 is methylated by PRMT1, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4), which in turn interferes with the differentiation process, and can contribute to the development of cancers. RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration | [19] |
Phosphorylation | METTL3 | CRC | ERK Interacts and Phosphorylates METTL3 and WTAP. ERK-dependent METTL3 stabilization affects cellular mRNA m6A methylation, which could contribute to tumorigenesis | [113] |
ISGylation | hnRNPA2B1 | Ovarian cancer | ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells | [114] |
CircEZH2 | IGF2BP2 | CRC | circEZH2 works as sponge of miR-133b to upregulate IGF2BP2 and blocks its ubiquitination-dependent degradation, thereby facilitating the proliferation and migration of CRC cells | [115] |
LncRNA LINRIS | IGF2BP2 | CRC | Upregulated LINRIS promote malignancy. Knockdown of LINRIS resulted in a decreased level of IGF2BP2 through ubiquitination of IGF2BP2 and attenuated MYC-mediated glycolysis in CRC cells | [116] |
Hsa_circ_0026134 | IGF2BP3 | HCC | Hsa_circ_0026134 expression promoted TRIM25- and IGF2BP3-mediated proliferation and invasion through sponging miR-127-5p | [117] |
miR503HG | HNRNPA2B1 | HCC | Decreased miR503HG exists in HCC. Enhanced expression of miR503HG inhibit HCC invasion and metastasis.miR503HG interact with HNRNPA2B1 and promoted its degradation via the ubiquitin-proteasome pathway, which reduced the stability of p52 and p65 mRNA, and simultaneously suppressed the NF-κB signaling pathway in HCC cells | [118] |
lncRNA CYTOR | HNRNPC | OSCC | Upregulated lncRNA CYTOR promote both migration and invasion as well as the EMT. lncRNA CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC | [119] |
circNEIL3 | IGF2BP3 | Glioma | Upregulated circNEIL3 stabilizes IGF2BP3 by preventing HECTD4-mediated ubiquitination and promotes tumorigenesis and progression | [120] |