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Tumor Discovery RNA-protein complexes deregulated in cancer

pathways, generating less-fit karyotypes. In gastrointestinal 4.4. Targeting the interaction between BC
cancers, the ncRNA colon cancer-associated transcript 2 components and the role of PTM
(CCAT2) plays a role in an RNA–protein complex formed This section highlights how mutations in cancer gene
by WD40-containing protein block-of-proliferation 1 fusions affect phase separation properties, potentially
(BOP1) and aurora kinase B (AURKB). This complex driving cancer initiation and progression. Insights into
disrupts chromosome segregation, causing chaotic cell this mechanism can inform therapy design for cancers
division. The CCAT2–BOP1–AURKB network is linked associated with aberrant phase separation. A central player
to 5-fluorouracil and oxaliplatin resistance. The presence in this process is the speckle-type POZ (Poxvirus and Zinc
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of active AURK, functional BOP1, and highly expressed finger) protein (SPOP), which serves as a substrate adaptor
CCAT2 RNA is crucial for driving chaotic cell division in for cullin 3 RING E3 ubiquitin ligase. SPOP facilitates the
this context.
ubiquitination and proteasomal degradation of oncogenic
Targeting ncRNAs often aims to overcome proteins, exerting anti-proliferative effects. Localized in
chemotherapy resistance. Researchers have tested nuclear speckles, SPOP oligomerization and substrate
nanoparticle-mediated RNA interference to knock down interaction induce the formation of nuclear phase-separated
ncRNAs using delivery systems such as nanoparticles, droplets, known as SPOP droplets. These droplets facilitate
liposomes, and PEG-conjugated particles. In triple- the ubiquitination of substrates like DAXX (death domain-
negative breast cancer (TNBC), the role of DANCR associated protein), marking them for proteasomal
ncRNA has been identified. Silencing DANCR with siRNA turnover. Studies have shown that the co-expression of
technology resulted in decreased proliferation and blocked DAXX with SPOP forms condensates enriched in SPOP/
tumor growth. Following DANCR downregulation, DAXX, facilitating DAXX ubiquitination and subsequent
EZH2 activity was restored, silencing the promoters of degradation. Cancer-associated SPOP mutations disrupt
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CD44 and ABCG2. Another strategy is to inhibit CIN the recruitment of DAXX and prevent the nucleation of
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and therapeutically address genetically frozen cancer SPOP/DAXX condensates, stabilizing DAXX instead.
cell populations. To provide oncologists with safe and DAXX, in turn, promotes tumor development by repressing
cost-effective medications, establishing production lines p53 activity. Its cytoplasmic and nuclear accumulation
capable of synthesizing large quantities of modified contributes to malignancy. 260
oligonucleotides is crucial. Genetic systems can be leveraged to deliver proteins
The European Medicines Agency has issued guidelines capable of dissolving p53 aggregates, potentially through
on RNA-based medicines, highlighting advances in mechanisms involving DAXX degradation, or to develop
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chemical modifications of ASOs, sequence engineering, crosslinked mimic condensates for selective drug delivery.
and tumor-specific delivery methods. In 2022, Synthetic peptides and nucleic acid-based oligonucleotides
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Benhamou designed an oncogenic noncoding RNA (e.g., RNA mimics, RNA sponges, siRNAs, and ASOs) hold
inhibitor by selecting optimal sequences from an RNA promise for targeting mutant phenotypes. Investigating the
library and comparing them with a DNA library. This dynamics of mutant p53 can enhance our understanding of
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pioneering work has laid the groundwork for developing protein misfolding and aggregation mechanisms. Novel drugs
efficient ncRNA-targeting drugs. targeting abnormal phase transitions and p53 aggregation may
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Patents have already been filed for targeting miR-22 have significant potential for clinical oncology applications.
in cancer and metabolism. ASO-based drugs are being Inhibition of mutant p53 aggregation by small molecules
developed for therapeutic applications. Examples include could effectively block tumor proliferation and migration.
oligonucleotides antisense to protein-coding genes Certain chemotherapeutics preferentially accumulate in
(e.g., BCL-2, VEGF, AP1) and antagomiRs targeting specific BCs due to interactions linked to the drug’s affinity
small RNAs, such as anti-miR-155 for cutaneous for its target. For instance, cisplatin tends to accumulate in
T-cell lymphomas and anti-miR-122. Miravirsen has transcriptional condensates, whereas tamoxifen localizes
demonstrated efficacy in primates for liver diseases, and in ER-alpha condensates. Estrogen-induced mediator
other oligonucleotides function as miRNA mimics. (MED) activity dilutes transcriptional condensates, along
Efforts to standardize RNA-based therapeutics and with tamoxifen concentrations in these BCs. Interestingly,
address technical challenges have been optimized to some therapeutics selectively interfere with condensates,
preserve bioactivity from production to delivery. Nucleic presenting opportunities to regulate compartments critical
acid-based drugs and delivery systems are now mature for disease development.
enough for industrial production, ensuring safe and Emerging evidence highlights the interplay between
efficient delivery to patients. ncRNAs and epigenetic enzymes, particularly through

Volume 3 Issue 4 (2024) 18 doi: 10.36922/td.4657