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Tumor Discovery RNA-protein complexes deregulated in cancer

structural scaffolds. 225,226 Blocking FTO activity with histone methylation at chromatin sites, enhancing
inhibitors such as FB23 and FB23-2, developed by Huang heterochromatin accessibility through inhibition of
et al., increased m6A levels and inhibited AML cell H3K27 methylation. Small sequences such as AC1NOD4Q
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growth. These inhibitors, which bind to FTO and block its and AC1Q3QWB have been developed to block EZH2’s
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demethylase activity, hold promise as therapeutic agents interaction with ncRNAs. These peptides prevent the
for AML. PRC2 complex from engaging ncRNAs and exerting
histone methylation. Administration of AC1Q3QWB
Inhibitors of the RNA-binding protein IGF2BP have
shown significant potential as anticancer agents. Recent increases the antitumor activity of 3-deazaneplanocin
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(DZNep), an S-adenosyl homocysteine hydrolase inhibitor
advancements in small molecules targeting m6A regulators targeting histone methyltransferases (HMTs), including
were reviewed by Feng et al. in 2024. Novel compounds EZH2. CC-90011, a reversible LSD1 inhibitor, has
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with high binding specificity and selectivity for m6A entered phase I human trials. This dual approach
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readers, including YTHFD1-YTHFD3 and YTHFC2, have targets histone methylation by inhibiting either histone
been proposed for therapeutic applications in AML, owing methyltransferases like EZH2 in cases of hypomethylation
to their antiproliferative effects. 227 or histone demethylases like LSD1 in cases of
In tumors with low m6A levels, such as certain breast hypodemethylation. In addition, the interaction between
cancers, m6A erasers exhibit increased activity. In these lncRNAs and EZH2 has been identified as a promising
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cases, small molecule activators of m6A writers, such as therapeutic target in cutaneous melanoma. METEOR-1, a
METTL3, may be effective. Depending on the tumor type phase I study of GSK3326595 (EPZ015938), a first-in-class
and ncRNAs involved, m6A writers may require either protein arginine methyltransferase 5 (PRMT5) inhibitor, is
inhibition or activation using suitable drugs. underway in advanced solid tumors. 228
4.1. Epigenetic modifications, cancer, and clinical Epigenetic and epitranscriptomic mechanisms
therapeutics significantly influence the levels of ncRNAs and
circRNAs, which play critical roles in cancer progression.
Phase separation properties in cellular processes depend Consequently, these enzymes must be targeted using
on amino acids favoring this transition, with charges and specific drugs. 231
influencing their behavior. Lysine and arginine residues,
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found in both histones and other associated proteins, are Numerous companies are actively developing novel
primary targets of epigenetic modifications. small molecules targeting epigenetic enzymes. Well-known
examples include HDAC inhibitors such as heliostat,
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Several inhibitors targeting histone mark writers, vorinostat, amidepsine, and panobinostat, which
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readers, and erasers have been identified and tested in is approved for T-cell lymphoma treatment, as well as
clinics trials. SET domain proteins, including lysine- thioamide, approved for treating leukemia and multiple
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specific demethylase 1 (LSD1) and the histone-lysine myeloma. 236
N-methyltransferase 2 family (MLL1-4SETD1A, SETD1B), 237
are prominent targets. In blood malignancies such as AML, effective
treatments have been achieved using 5-azacitidine,
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Lysine methyltransferase (KMT) enzymes, such as EZH1 decitabine, and guadecitabine, which target DNMTs.
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and EZH2, are integral to the PRC complex, relying on the Similarly, inhibitors of m5C methylase, such as azacitidine,
catalytic SET domain. KMT activity, including that of NSD1, decitabine, and cytidine analogs, are approved therapies
depends on S-adenosylmethionine (SAM) availability, which for blood tumors.
inversely correlates with nicotinamide-N-methyltransferase A recent study on long noncoding RNAs (lncRNAs) has
(NNMT) activity. NNMT produces 1-methyl nicotinamide, provided insight into their roles in therapeutic resistance.
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a methyl sink for SAM-derived methyl groups. FIDAS-5, a For example, APAF1-binding lncRNA (ABL) promotes
methionine-adenosyltransferase (MAT2A) inhibitor, has proliferation and drug resistance in gastric cancer by
been shown to reduce tumor size in 5TGM1 murine cells. inhibiting apoptosis and caspase activation. It achieves this
MAT2A inhibition by FIDAS-5 enhances the effects of by binding to APAF1 and preventing its interaction with
bortezomib, a proteasome inhibitor, in MM.
cytochrome c. Encapsulated liposomal siRNAs targeting
EZH2 overexpression has been observed in lymphoma ABL have been shown to restore chemotherapy sensitivity.
and other cancers. Tazemetostat, an EZH2 inhibitor, has Another example is ARHGAP5-AS1, which facilitates
been approved for treating epithelioid sarcoma. 227 Novel m6A modification of ARHGAP5 mRNA, stabilizing it
inhibitors have been designed to block EZH2 and histone- by recruiting the m6A writer METTL3 in the cytoplasm,
modifying enzymes. Targeting EZH2 activity prevents thereby inducing chemoresistance in gastric cancer.
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Volume 3 Issue 4 (2024) 16 doi: 10.36922/td.4657