Table 1.
The role and mechanisms of m6A modulators in human cancer.
| m6A Modulators | Cancer Types | Roles | Mechanisms | Ref. |
|---|---|---|---|---|
| METTL3 | Osteosarcoma | Oncogenic functions | m6A methylation level and METTL3 expression are both upregulated in osteosarcoma tissues and cell lines. Promotes cancer cell proliferation and metastasis by regulating ATAD2 | [79,112] |
| Colorectal cancer (CRC) |
Oncogenic functions | METTL3 can stabilize HK2 and GLUT1 expression in CRC through an m6A-IGF2BP2/3-dependent mechanism. | [80] | |
| METTL3 maintains SOX2 expression through an m6A-IGF2BP2-dependent mechanism in colorectal cancer cells, and can work as a potential biomarker panel for prognostic prediction in CRC. | [81] | |||
| METTL3/miR-1246/SPRED2 axis plays an important role in tumor metastasis. | [82] | |||
| Bladder cancer | Oncogenic functions | METTL3, significantly increased in bladder cancer, is correlated with poor prognosis of bladder cancer patients, and may have an oncogenic role in bladder cancer through positively modulating the pri-miR-221/222 process in an m6A-dependent manner. | [83] | |
| METTL3-mediated m6A modification promotes bladder cancer progression through AFF4/NF-κB/MYC signaling network. | [84] | |||
| Hepatocellular carcinoma (HCC) |
Oncogenic functions | METTL3 is frequently upregulated in human HCC and contributes to HCC progression through repressing SOCS2 expression in an m6A-YTHDF2-dependent mechanism. | [85] | |
| Acute myeloid leukemia (AML) |
Oncogenic functions | Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation, which is necessary for the maintenance of the leukemic State. | [73] | |
| METTL3 is frequently upregulated in human AML, and controls expression of c-MYC, BCL-2, and PTEN in an m6A-dependent manner. | [86] | |||
| Gastric cancer | Oncogenic functions | METTL3, overexpressed in gastric cancer, is correlated with poor prognosis of gastric cancer, and required for the epithelial-mesenchymal transition (EMT) process in vitro and for metastasis in vivo. | [87] | |
| Elevated METTL3 expression can promote tumor angiogenesis and glycolysis in gastric cancer through m6A modification of HDGF mRNA. | [88] | |||
| Pancreatic cancer | Oncogenic functions | METTL3 is enriched in human pancreatic cancer, and can promote cell proliferation and invasion of pancreatic cancer cells. | [89] | |
| METTL3 can promote the chemoresistance and radioresistance of pancreatic cancer cells through regulation of several critical pathways, including MAPK cascades, ubiquitin-dependent process, and RNA splicing. | [90] | |||
| Lung cancer | Oncogenic functions | METTL3 is upregulated in human lung adenocarcinoma, and can promote cell proliferation, survival, and invasion of human lung cancer cells through enhancing translation of certain mRNAs, including EGFR and TAZ. | [74] | |
| Endometrial cancer | Tumor suppressive functions | About 70% of endometrial tumors show reduced total m6A mRNA methylation, which is mediated by either decreased METTL3 expression or METTL14 loss-of-function mutation, and reduced m6A methylation could promote cancer cell growth through activation of the AKT pathway. | [91] | |
| Glioblastoma | Tumor suppressive functions | Knockdown of METTL3 or METTL14 induces changes in mRNA m6A enrichment, and enhances cell proliferation of glioblastoma stem cells (GSCs) through altering expression of several oncogenes and tumor suppressors, such as ADAM19 and CDKN2A. | [92] | |
| Oncogenic functions | METTL3, upregulated in GSCs, is essential for GSC maintenance, and stabilizes SOX2 mRNA in an m6A-dependent manner. | [93] | ||
| METTL14 | Acute myeloid leukemia (AML) |
Oncogenic functions | METTL14 is required for development and maintenance of AML through regulating its mRNA targets, including MYB and MYC in an m6A-dependent manner. | [65] |
| Renal cancer carcinoma (RCC) |
Tumor suppressive functions | METTL14 is downregulated in RCC tissues, and could abrogate P2RX6 protein level in an m6A-dependent manner. | [94] | |
| Hepatocellular carcinoma (HCC) |
Tumor suppressive functions | METTL14, downregulated in HCC, is associated with metastasis through modulating the processing of miR-126 in an m6A-dependent manner, and works as a prognostic factor in HCC. | [95] | |
| METTL16 | Colorectal cancer (CRC) |
Association with worse OS in rectal adenocarcinoma | METTL16 is abundantly expressed in colon adenocarcinoma, and associated with the clinical outcomes of CRC patients. | [113] |
| Mutational ITH and frameshift mutations with MSI-H | METTL16 harbors mutational intratumor heterogeneity (ITH) as well as the frameshift mutations in CRC with high microsatellite instability (MSI-H). | [114] | ||
| WTAP | Hepatocellular carcinoma (HCC) |
Oncogenic functions | WTAP, highly expressed in HCC, is correlated with poor prognosis of HCC patients, and can promote cell proliferation of HCC cells through suppression of ETS1 in an m6A-dependent manner. | [98] |
| FTO | Acute myeloid leukemia (AML) |
Oncogenic functions | FTO is highly expressed in AMLs, and can enhance oncogene-mediated cell transformation and leukemogenesis through regulating its mRNA targets such as ASB2 and RARA in an m6A-dependent manner. | [66] |
| Lung squamous cell carcinoma (LUSC) |
Oncogenic functions | FTO is a prognostic factor for LUSC, and can facilitate tumor progression in LUSC through regulating MZF1 expression in an m6A-dependent manner. | [99] | |
| ALKBH5 | Breast cancer | HIF-depended enrichment of breast cancer stem cells (BCSCs) | Increased NANOG mRNA expression is induced by hypoxia in an HIF- and ALKBH5-dependent manner, which increased specification of BCSCs. | [100] |
| Glioblastoma | Maintaining tumorigenicity of GSCs | ALKBH5 is highly expression in GSCs, and maintains tumorigenicity through regulating FOXM1 expression in an m6A-dependent manner. | [101] | |
| Pancreatic cancer | Tumor suppressive functions | ALKBH5 inhibits pancreatic cancer motility through regulating lncRNA KCNK15-AS1 expression in an m6A-dependent manner. | [102] | |
| YTHDF1 | Colorectal cancer (CRC) |
Oncogenic functions | YTHDF1, highly expressed in CRC, is correlated with poor prognosis of CRC patients, and can promote cell proliferation of CRC cells. | [103] |
| YTHDF2 | Cervical cancer | Tumor suppressive functions | lncRNA GAS5-AS1 upregulates GAS5, a tumor suppressor, through an YTHDF2-dependent mechanism. | [105] |
| Acute myeloid leukemia (AML) |
Oncogenic functions | YTHDF2, overexpressed in human AML, is required for disease initiation, and decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of self-renewing leukemic stem cell (LSC) function, including TNFR2. | [106] | |
| Hepatocellular carcinoma (HCC) |
Tumor suppressive functions | Hypoxia induces downregulation of YTHDF2 in HCC cells, and YTHDF2 overexpression suppresses cell proliferation of HCC cells through inactivation of MEK and ERK. | [108] | |
| YTHDC1 | Prostate cancer | Potential tumor biomarker | The oncogene MTDH interacts with YTHDC1, KHDRBS1, and KHDRBS3, and modulates alternative splicing. | [104] |
| YTHDC2 | Colon cancer | Promoting cancer metastasis | YTHDC2 can promote cancer metastasis through promoting HIF-1α. | [109] |
| IGF2BP1 | Ovarian, skin, lung, liver cancer | Oncogenic functions | IGF2BP1 can promote the transcriptional regulator SRF-dependent transcription in an m6A-dependent manner. | [110] |
| IGF2BP2 | Pancreatic cancer | Oncogenic functions | IGF2BP2, highly expressed in pancreatic cancers, is correlated with poor prognosis of pancreatic cancer patients, and can promote cell proliferation of pancreatic cancer cells through DANCR. | [111] |