Table 2 Functions of m6A regulators related to the PI3K/AKT signaling pathway in cancer
From: Role of m6A modification in regulating the PI3K/AKT signaling pathway in cancer
Cancer type | Model | Regulator | Expression of regulator | Targets | Function | Mechanism | References |
|---|---|---|---|---|---|---|---|
Pancreatic cancer | In vitro/in vivo | METTL3 | Up | DDX23 | Promote gemcitabine resistance | Modifying DDX23 mRNA m6A methylation through PI3K/AKT signaling activation | [130] |
In vitro/in vivo | METTL3/METTL14 | Up | PTEN | Promote cell proliferation, EMT and tumorigenesis in PC cells | MiR-380-3p activated the AKT pathway in cancer cells by degrading PTEN | [131] | |
Gastric cancer | In vitro/in vivo | ALKBH5 | Down | – | Promote apoptosis of gastric cancer cells | Attenuating the PI3K/AKT pathway | [136] |
In vitro/in vivo | METTL3 | Up | CUL4B | Promote proliferation and invasiveness | Transcriptionally repressing miR-22-3p and miR-320a | [35] | |
In vitro | METTL14 | Down | CDH1 | Promote proliferation and invasiveness | Reduce RNA m6A methylation activated oncogenic Wnt/PI3K/AKT signaling | [23] | |
Gallbladder cancer | In vitro/in vivo | METTL3 | Up | PTEN | Promote proliferation and invasiveness | DCA-induced downregulation of miR-92b-3p inhibited oncogenic PI3K/AKT signaling by elevating PTEN | [198] |
Colorectal cancer | In vitro/in vivo | METTL3 | Up | EphA2/VEGFA | Promote proliferation and invasiveness | METTL3 methylated EphA2 and VEGFA induces VM formation by activating both PI3K/AKT and ERK1/2 signaling | [142] |
In vitro/in vivo | METTL14 | Down | SOX4 | Inhibits tumor metastasis | Promote SOX4-mediated EMT and activate SOX4-mediated PI3K/Akt signaling pathway | [143] | |
Hepatocellular carcinoma | In vitro | ALKBH5 | Down | PAQR4 | Suppress cancer cell proliferation, migration, and invasion | Downregulate PAQR4 expression in an m6A-dependent manner, suppress PI3K/AKT pathway activation | [151] |
In vitro/in vivo | METTL14 | Down | EGFR | Promote proliferation and invasiveness | Inhibit cancer cell migration, invasion and EMT by modulating the EGFR/PI3K/AKT signaling pathway in an m6A-dependent manner | [152] | |
In vitro/in vivo | ALKBH5 | Down | SHIP2 | Promotes cancer cell proliferation and metastasis, thereby conferring drug chemoresistance. | DestabilizedSHIP2 by enhancing E3 ubiquitin ligase CUL4A ubiquitination-dependent SHIP2 degradation | [153] | |
In vitro/in vivo | FTO | Up | TGF-β2 | Poor differentiation, and metastasis in patients with clinical hepatocellular carcinoma | RALYL could regulate HCC stemness through STAT3-dependent TGF-β2 upregulation | [154] | |
– | IGF2BP1 | Up | ATG16L1 | Promote cell proliferation, migration and invasion | Adsorption of miR-346 and miR-874-3p to activate the PI3K/AKT/mTOR signaling pathway | [155] | |
– | YTHDF1 | Up | – | Promote the migration and invasion | Activate PI3K/AKT/mTOR signaling pathway and inducing EMT | [34] | |
Ovarian cancer | In vitro/in vivo | METTL3/RHPN1-AS1 | Up | – | Promote cell viability, migration, invasion and tumor growth | METTL3-mediated m6A modification of RHPN1/AS1 accelerates cisplatin resistance in ovarian cancer by activating PI3K/AKT pathway | [159] |
In vitro/in vivo | METTL3 | Up | LETM1 | Promote cancer cell proliferation and metastasis | Sponge miR-596, increase LETM1 expression, and activate the FAK/PI3K/AKT signaling pathway | [160] | |
Cervical cancer | In vitro | METTL14 | Down | – | Inhibit the growth and invasion of cervical cancer | Suppress the PI3K/AKT/mTOR signaling pathway by decreasing the phosphorylation of Akt and mTOR | [163] |
Osteosarcoma | In vitro/in vivo | WTAP | Up | HMBOX1 | Promote proliferation and invasiveness | WTAP/HMBOX1 regulate osteosarcoma growth and metastasis by regulating the PI3K/AKT pathway | [195] |
Renal cell cancer | In vitro/in vivo | IGF2BP | Up | EGR2 | Promote proliferation and invasiveness | Promote kidney tumorigenesis by activating the PI3K/AKT pathway | [168] |
In vitro/in vivo | METTL14 | Down | PTEN | Promote the cell proliferation, migration and tumor progression | Restrain PTEN expression in clear cell renal cell carcinoma, leading to the tumor progression by activating the PI3K/AKT signaling pathway | [167] | |
Bladder cancer | In vitro/in vivo | YTHDC1 | Down | PTEN | Promote proliferation and invasiveness | Lower YTHDC1 destabilizes PTEN mRNA, activates AKT-associated DNA damage response, and attenuates cisplatin-induced DNA damage | [171] |
Prostate cancer | In vitro/in vivo | METTL3 | Up | MALAT1 | Promote proliferation and invasion | MALAT1 promotes the activation of PI3K/AKT signaling and abrogates METTL3 knockdown-induced PI3K/AKT signaling inactivation in prostate cancer cells | [175] |
In vitro/in vivo | YTHDF1 | Up | PLK1 | Promote proliferation, migration, and invasion | YTHDF1 regulates the PI3K/AKT signaling pathway through PLK1 | [176] | |
Glioblastoma | In vitro/in vivo | IGF2BP3 | Up | RPN2 | Blocking WEE2-AS1 expression improved the therapeutic sensitivity to dasatinib | WEE2-AS1 promotes RPN2 protein stabilization by preventing CUL2-mediated RPN2 K322 ubiquitination | [179] |
Retinoblastoma | In vitro/in vivo | METTL3 | Up | – | Promote cell proliferation, migration and invasion of retinoblastoma cells | The PI3K/AKT/mTOR pathway regulates the translation of mRNAs that encode pro-oncogenic proteins, leading to malignant cell survival | [184] |
Nasopharyngeal carcinoma | In vitro/in vivo | METTL3 | Up | MiR-10-100p | Promote proliferation and invasiveness | ZFAS1 can regulate the expression of ATG10 through sponge miR-100-3p to affect the level of autophagy | [188] |
In vitro/in vivo | YTHDC2 | Up | IGF1R | Promote radiotherapy resistance of nasopharyngeal carcinoma cells | Activate the PI3K/AKT/S6 pathway by regulating the translation of IGF1R mRNA | [189] | |
Lung cancer | In vitro | METTL3 | Down | A549/H1299 | Inhibit proliferation and migration | Induce apoptosis by inhibiting activation of the PI3K signaling pathway | [192] |
In vitro | IGF2BP2 | Up | – | Promote angiogenesis and metastasis | Improve the RNA stability of FLT4 through m6A modification, thereby activating the PI3K/Akt signaling pathway | [193] |