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Tumor Discovery RNA-protein complexes deregulated in cancer

at actively transcribed genes. It induces phase separation, 3. NEAT1 and paraspeckles
leading to droplets with distinct physical properties.
Acetylation of chromatin promotes a unique phase- Speckles and parapeckles regulate protein complexes
separated state, with droplets that exhibit specific physical competing with oncogene signaling. For instance, the
characteristics. Acetylated chromatin is immiscible with interaction between sirtuin1 (SIRT1) and deleted in
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heterochromatin containing non-acetylated chromatin. breast cancer 1 (DBC1), which then releases SIRT1 and
enhances its deacetylation activity on p53. Consequently,
This property reflects the segregation of chromatin into the deacetylation of p53 reduces the transcription of its
subdomains within the cell. Chromatin forms phase- downstream target genes and promotes cell proliferation.
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separated condensates, grouping regions with modified Paraspeckles are nuclear BCs that appear as chains of
and unmodified chromatin states.
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spheroids. 103-107 They involve over 60 proteins and one
Repressed genes are located in heterochromatin RNA, namely, nuclear paraspeckle assembly transcript 1
regions marked by H3K27 methylation and non-acetylated (NEAT1). There are two variants of NEAT1: NEAT1_1,
nucleosomes, whereas active genes are associated with which is 3.7 kb in length, and NEAT1_2, which is 23 kb
acetylated nucleosomes in euchromatin. Euchromatin and in length. Nascent 2,300-nucleotide–long NEAT1_2
heterochromatin regions remain dynamically accessible to transcripts recruit nuclear RNA-binding proteins to
regulation by chromatin-modifying enzymes and protein construct paraspeckles. NEAT1_2 is regulated by p53 and
readers of modified nucleosomes. 36,37 is a direct target of p53. It is induced by stress related
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109
Chrom-Seq methods utilize biotinylation tags combined to DNA damage and replication stress. NEAT1_1 is
with peptides that localize to specific chromatin regions associated with cancer metabolism, enhanced glycolysis,
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and histone marks. One example is the mouse CBX7 and the Warburg effect. NEAT1_2, which is essential
peptide (containing a chromodomain between amino for paraspeckle formation, recruits and retains proteins
acids 2 and 76), and another is the Drosophila polycomb required for their assembly and is particularly noteworthy
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(dPC) protein. Fan et al. used the Chrom-Seq method due to its presence in different variants. NEAT1_2 is
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to identify RNAs proximal to H3K27me3 marks and expressed in up to 50 copies per paraspeckle. The number
validated their findings using RNA-IP quantitative PCR of paraspeckles in a cell varies by cell type, with HeLa
(RIP-qPCR). They identified 542 H3K27me3-associated cells containing 13 – 17 foci/nucleus and NIH3T3 mouse
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ncRNAs. These histone marks define transcribed loci on fibroblasts containing 5 – 10 foci/nucleus. Eight proteins
euchromatin. Other ncRNAs that associate with H3K9me3 are critical for paraspeckle nucleation: non-POU domain-
marks indicate repressed genes on heterochromatin. In containing octamer binding (NONO); splicing factor rich
some cases, ncRNAs are associated with both active and in proline and glutamine (SFPQ); paraspeckle protein
repressive PTMs; such ncRNAs are known as bivalent component 1 (PSPC1); heterogeneous nuclear RNPs
chromatin-associated RNAs. Double-site–interacting HNRNPA1, HNRNPA2, HNRNPK, and HNRNPH3;
RNAs, which localize to both H4K20me3 and H3K4me3 fused in sarcoma (FUS); DAZAP1; Brahma homolog
marks, play roles in chromatin organization and RNA component of SWI/SNF (BRG1); and the RNA-binding
processing. H4K20me3-interacting RNAs are linked to protein RBM14 (Figure 2). Notably, knockdown of these
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cell differentiation, whereas H3K4me3-interacting RNAs critical proteins leads to paraspeckle disintegration.
are associated with metabolism and RNA processing. In a search for paraspeckle modulators, An et al. identified
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H4K20me3 has been recognized as a key epigenetic several dual PI3K/mTOR inhibitors—Torin 1, PP242,
regulator of chromatin structure and disease. 37 LY3023414 (samotolisib), and INK128-as potent negative
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A schematic summary of the various roles of ncRNAs modulators of paraspeckles. Rapamycin kinase T (ORK)
in BC functioning is presented in a series of tables. Several inhibitors were also shown to inhibit PI3K. Additional
of these ncRNAs have been the subject of cancer-related dual PI3K/mTOR inhibitors, such as GSK1059615 and
studies. Tables 1-3 describe ncRNAs that act alongside CAY10626, as well as the PI3K/mTOR/DNA-PK inhibitor
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protein complexes, guiding them to the target gene sites. PI-103, which has been used in clinical trials for chronic
Table 1 outlines ncRNAs involved in chromatin regulation, lymphocytic leukemia (CLL), similarly reduced either the
which guide Polycomb (PcG) repressive complexes (PRC) NEAT1_2 area or the number of paraspeckles.
in PcG bodies to specific gene promoters for silencing. NEAT1_2-dependent clusters influence the interaction
Table 2 describes ncRNAs that guide DNMT1 for CpG of proteins like FUS, which aggregate around RNA, with
methylation at specific promoters. Table 3 details ncRNAs the RNA-binding protein RBP14 and paraspeckle proteins
that guide chromatin-activating complexes and histone PSPC1, NONO, and SFPQ. During tumor progression,
modification enzymes for gene activation. NEAT1_2, along with NONO, RBM14, and PSPC1, is

Volume 3 Issue 4 (2024) 5 doi: 10.36922/td.4657