Table 1.
Summary of mechanistic studies into the role of the METTL3-m6A epitranscriptome in epithelial cancers, and particular SCCs.
| SCC | Mechanism(s) | Reference(s) |
|---|---|---|
| cSCC | Increased METTL3-m6A promotes upregulation of p63 and K14, downregulation of K10, and cell proliferation | [58] Zhou, R. et al., 2019 |
| HNSCC | METTL3 adds m6A to cMyc mRNA to enhance its stability and promote proliferation, invasion and migration in vitro and tumorigenicity in vivo | [71] Zhao, W. et al., 2020 |
| METTL3 adds m6A to BMI1 mRNA to promote its translation in conjunction with IGF2BP1 to drive tumorigenesis | [72] Liu, L. et al., 2020 | |
| Increased METTL3/14-m6A enhances LNCAROD which protects the oncogenic protein YBX1 from degradation to drive tumorigenesis | [68] Arumugam, P. et al., 2021 | |
| CESC | FTO is frequently overexpressed and removes m6A to lead to the increased translation of MYC, E2F1, and b-catenin, promoting both radiotherapy resistance and poor survival | [76] Zou, D. et al., 2019; [77] Zhou, S. et al., 2018 |
| LUSC | High YTHDF1 expression promotes tumorigenesis in murine models, though in humans increased expression associated with better responses to chemotherapy and improved clinical outcomes | [80] Shi, Y. et al., 2019 |
| FTO overexpression removes m6A to lead to the increased translation of MZF1 which promotes proliferation and invasion | [79] Liu, J. et al., 2018 | |
| BLCA | Increased METTL3-m6A in conjunction with YTHDF1 and YTHDF3 promotes ITGA6 mRNA translation which enhances the growth and metastasis of BLCA cells | [85] Jin, H. et al., 2019 |
| Increased METTL3 associated with worse prognosis and survival, promotes increased miRNA and CDCP1 oncogene expression to enhance malignant transformation in vitro and in vivo | [83] Han, J. et al., 2019; [84] Yang, F. et al., 2019 | |
| ESCC | Increased METTL3 associated with worse survival and promotes proliferation via increasing AKT expression | [87] Hou, H. et al., 2020 |
| YTHDC2 variants associated with ESCC and its inhibition blocks ESCC cell proliferation | [88] Yang, N. et al., 2020 | |
| Increased reader expression (HNRNPA2B1) correlates with tumor diameter and lymphatic metastasis and promotes disease and its knockdown can block proliferation, migration, and invasion | [89] Guo, H. et al., 2020 |
While there are some underlying commonalities, the findings give a sampling of the diverse mechanisms by which dysregulation of the writers, readers, and erasers of m6A can promote cancer in a context- and tissue-specific fashion. Cancers listed include bladder cancer (BLCA), cutaneous SCC (cSCC), head and neck SCC (HNSCC), esophageal SCC (ESCC), cervical SCC (CESC), and lung SCC (LUSC).