Page 73 - TD-3-4

Tumor Discovery RNA-protein complexes deregulated in cancer

regulator independent of its RNA m6A methyltransferase recognition by m6A erasers. This variability, coupled
activity, 191,192 as it colocalizes with repressive H3K27me3 with cell type-specific interactions with m6A writers,
marks on chromatin. METTL14 binds to H3K27me3 and readers, and erasers, contributes to differences in cancer
KDM6Brecruits facilitating H3K27me3 demethylation, a susceptibility and progression. Different cancers exhibit
process essential for the transition from embryonic stem distinct expression levels of m6A-modifying enzymes,
cells to differentiated cells. Another methyltransferase further influencing cancer development and therapeutic
193
complex (MTC) is formed by the association of RNA- outcomes.
binding motif protein 15 (RBM15), vir-like m6A Similar to ncRNAs, there is a dynamic crosstalk
methyltransferase-associated protein (VIRMA), zinc between circRNAs and m6A modifications. CircRNAs
finger CCHC-type containing 4 (ZCCHC4), and zinc impact cancer response to chemotherapeutics through
finger CCCH-type containing 13 (ZC3H13). 27 mechanisms such as modulating drug transport, DNA
Regarding internal m7G (N7-methylguanosine) writers, repair, apoptosis, the TME, autophagy, EMT, cancer stem
METTL1 forms a protein complex with WD repeat domain cells, and glycolysis. 209
4 (WDR4). This complex is active on tRNAs, rRNAs,
mRNAs (enhancing mRNA translation), and miRNAs. 4. Epitranscriptome regulation of ncRNAs
The insulin-like growth factor 2 mRNA-binding protein and cancer therapeutics
(IGF2BP) family serves as readers of m6A modifications, Recent databases have compiled information on ncRNAs
regulating the stability of m6A-modified mRNAs. m6A involved in epigenetic regulation. 207,208 A significant
influences RNA-driven phase separation by altering resource, curated by Yulia Medvedeva’s laboratory at the
RNA–RNA and RNA–protein interactions. For example, Institute of Bioengineering, Russian Academy of Science,
194
the loading of m6A readers facilitates phase separation. lists over 4,100 such ncRNAs and is accessible at https://
Notably, IGFBP2/3 act as m6A readers, binding ncRNAs github.com/lab-medvedeva/himorna-frontend. Similar
and promoting the stability of m6A-modified mRNAs. to how amino acid charges and PTMs confer new
27
209
Other m6A readers include eukaryotic initiation factor properties, epitranscriptomic modifications in ncRNAs
(eIF3), proteins of the heterogeneous nuclear RNP influence interaction strength, base pairing, and RNA
(HNRNP) family, and YTHDF1 and YTHDF2, which stability.
contain the YT521-B homologous (YTH) domain.
The METTL3 inhibitor STM2457 entered phase
The cytoplasmic protein YTHDF2 binds to m6A marks, I clinical trials in 2022, demonstrating inhibition of
either leading to degradation of m6A-modified RNAs proliferation in AML. S-adenosylmethionine (SAM), an
211
by erasers or facilitating the localization and translation essential cofactor, is required for both DNMT1 (a DNA
of bound mRNAs through interactions with translation methylating enzyme) and METTL3. 212,213 METTL3A, a
initiation factors. In the nucleus, YTHDC1 regulates pre- component of the m6A writer complex, is a key target in
mRNA splicing by recruiting splicing factors. cancers with elevated m6A levels. METTL3 inhibitors,

Demethylases such as fat mass- and obesity-associated including STC-15, have been tested in clinical trials. 214
protein (FTO) and alkylation repair AlkB homolog protein Various epitranscriptomic modifications of ncRNAs
5 (ALKBH5) remove m6A modifications. PSPC1, a affect RNA stability and function in cancer. Researchers
regulatory subunit of ALKBH5, binds to K235-acetylated have developed drugs targeting the writers, readers, and
ALKBH5, enhancing its recognition of m6A-modified erasers of m6A modifications. 211-214,216 Promising anticancer
RNAs and promoting its erasing activity. Elevated K235 effects have been reported for inhibitors targeting the
acetylation of ALKBH5 is observed in cancers and is METTL3–METTL14 methylation complex. These
linked to tumorigenesis. Table 5 highlights the ncRNAs inhibitors exhibit diverse chemical structures, such as
132
and circRNAs regulated by m6A-associated enzymes. adenine derivatives, sinefungin, UZH derivatives, CDIBA
derivatives, STM2457, and eltrombopag. In addition,
217
An internal N7-methylguanosine (m7G) modification
in ncRNAs has been identified as a significant factor in compounds such as mitoxantrone, suramin, KH3, and
eltrombopag inhibit the RNA-binding domain of ELAVL/
resistant acute myeloid leukemia (AML). However, HuR, demonstrating antiangiogenic properties. Notably,
188
217
limited information exists on m7G readers and erasers.
various METTL3 inhibitors entered phase 1 clinical trials
Each ncRNA possesses unique properties, with m6A for AML in 2022. 211,214,217 Researchers have explored two
modifications sometimes enhancing stability through main approaches: developing m6A writer inhibitors
217
interactions with m6A readers, while in other cases, and allosterically activating m6A writing complexes.
they make ncRNAs susceptible to degradation through Drug compounds targeting METTL14, a transcriptional
Volume 3 Issue 4 (2024) 14 doi: 10.36922/td.4657