Over the past decade, a great number and variety of RMPs have been implicated in various human cancers.
Recent literature is expanding our view of the spectrum of RMPs that are implicated in different human cancers. Of the various modifications to RNA, m6A is by far the most abundant, and much of the recent literature has focused on identifying alterations in the m6A-associated RMPs in human cancers. Beyond m6A and the writers/erasers that create this mark, other RMPs have been implicated in cancer, including those that modify tRNA. The table below, taken from our recent review article in Nature Reviews Drug Discovery gives just a small sampling of the variety of RMPs and the reactions they perform, which have been implicated in human cancers. Examples of RMPs that are implicated in human cancers:
| RMP | Protein
Activity | Cancer Implication |
| METTL3/METTL14 | m6A methylation |
| Depletion promotes differentiation and delays leukemia progression in AML1 |
| Overexpression inhibits growth and self-renewal of glioblastoma stem cells (GSCs) |
| Knockdown radiosensitizes GSCs in vitro and inhibits their in vivo growth |
| Promotes hepatocellular carcinoma (HCC) progression |
| Knockdown inhibits translation of key oncogenes |
| Knockout prevents T-cell differentiation |
|
| METTL1 | m7G methylation (tRNA) | Modulates chemosensitivity to 5-FU |
| METTL6 | m6G methylation (tRNA) | Amplified in luminal-subtype breast cancer |
| NSUN2 | m5C methylation (mRNA, tRNA) |
| Copy-number gain in breast cancer and other tumors |
| Mediates MYC-induced proliferation; increased expression in tumors |
| Promotes cancer cell migration through RNA methylation-mediated repression of miR-125b |
|
| NSUN4 | m5C methylation (rRNA) | Identified as breast and prostate cancer risk loci through GWAS |
| TRMT2A | m5U methylation (tRNA) | Overexpressed in subset of HER2+ breast cancer, associated with increased risk of recurrence |
| TRMT12 | o2yW wybutosination (tRNA) | Amplified and overexpressed in breast cancer |
| BCDIN3D | 5’ phosphate methylation (rRNA) | Knockdown greatly reduces invasiveness potential of triple negative breast cancer cells |
| AlkBH5 | m6A demethylation (mRNA) |
| AlkBH5 elevated under hypoxia in breast cancer stem cells, and knockdown impairs tumor formation |
| AlkBH5 knockdown inhibits in vitro and in vivo growth of GSCs |
|
| YTHDC2 | m6A reader | Promotes colon cancer metastasis |
| YTHDF2 | m6A reader |
| Promotes proliferation but inhibits metastasis of pancreatic cancer |
| Translocation with RUNX1 in AML |
|
Taken from Boriack-Sjodin et al. Nature Reviews Drug Discovery, (2018).
The team at Accent is working towards validation of select targets and expanding our understanding of the roles of RMPs in oncogenesis. We are combining established gene editing methods (e.g., CRISPR-Cas9) with proprietary chemical biology methods to probe and establish these relationships more firmly, as a foundation for our drug discovery and development efforts.