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Tumor Discovery RNA-protein complexes deregulated in cancer

and their subcellular compartmentalization, particularly (EMT) and stemness. It sustains Myc activation
within paraspeckles. 125 and promotes tumor growth in breast and prostate
PSPC1 potentiates IGF1R expression, enhancing cell cancer. PSPC1 enhances the secretion of transforming
adhesion and motility. It has been demonstrated that every growth factor-β1 (TGF-β1) through interactions with
component of paraspeckles is involved in this process. phosphorylated nuclear Smad2/3. PSPC1 promotes a TGF-
Knockdown experiments of PSPC1-interacting paraspeckle β1 prometastatic switch by altering the binding preference
components, including NONO, FUS, and NEAT1, have of Smad2/3 from tumor suppressor genes to prometastatic
137,138
shown that these are essential for PSPC1-regulated genes.
IGF1R expression. Focal adhesion kinase and sarcoma In CRC, LOC105369504 expression is downregulated,
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kinase (Src) signaling pathways cooperate to increase cell leading to the inhibition of proliferation, invasion, migration,
adhesion and motility in HCC. Insulin-like growth factor and EMT. LOC105369504 binds to PSPC1, regulating PSPC1
1 receptor (IGF1R), a membrane tyrosine kinase receptor, stability through the ubiquitin-proteasome pathway. 139
is a targetable molecule overexpressed in tumor metastasis, The pro-oncogenic activities of PSPC1 are closely linked
drug resistance, and poor prognosis across various cancers. to those of the orphan nuclear receptor 4A1 (NR4A1,
In colorectal cancer (CRC), MALAT1 binds to SFPQ,
releasing the oncogene PTBP2 from the SFPQ/PTBP2 Nur77). NR4A1 knockdown decreases PSPC1 expression
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complex. In the same cancers, SFPQ depletion has been in various cell lines. Bisindole-derived NR4A1 antagonists
shown to be synthetically lethal in the presence of BRAF (CDIMs) also induce PSPC1 downregulation in breast
140
131
V600E mutations. In addition, SFPQ promotes lung cancer. Following NR4A1 silencing, genes associated
with cancer stemness and EMT are also downregulated.
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cancer malignancy and contributes to the proliferation,
migration, and invasion of HCC. SFPQ condensates also NEAT1_2-dependent clusters influence how proteins
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sequester SMAD4, thereby preventing tumor-suppressive such as FUS, which aggregate around RNA, interact
signaling through the TGF-β pathway. PSPC1 interacts with the RNA-binding protein RBP14 and paraspeckle
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with lysine demethylase KDM5C, and both proteins proteins PSPC1, NONO, and SFPQ. Activation of the
are recognized as oncogenic factors in prostate cancer mechanistic target of rapamycin (mTOR) reduces NEAT1_2
(PCa). Inhibition of KDM5C and PSPC1 using specific transcription, diminishes paraspeckles, and releases NONO,
compounds shows potential as a therapeutic strategy for SFPQ, and RBP14, which are essential for RNA splicing.
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PCa. 132,133 In sporadic amyotrophic lateral sclerosis (ALS), Table 4 provides a detailed overview of ncRNAs necessary
NONO and PSPC1 remain localized within the nuclei of for the formation of different BC types.
motor neurons, whereas SFPQ and FUS exhibit nuclear
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loss, and TDP-43 displays cytoplasmic localization. 135 3.1. Speckles and MALAT1
RNA-binding proteins (RBPs) are critical components The ncRNA MALAT1 is a key RNA constituent of nuclear
of BCs. Many RBPs colocalize with RNA polymerase II speckles and is overexpressed in cervical, colorectal, lung,
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(Pol II) at promoter and enhancer loci. The paraspeckle breast, liver, and bladder tumors. Elevated MALAT1
protein PSPC1 utilizes RNAs as multivalent molecules to expression is associated with poor prognosis and metastasis
form transcription condensates, which are followed by the formation in lung cancer and other tumors. 143,144 Cells with
phosphorylation and release of Pol II. 136 aberrant MALAT1 expression exhibit various dysregulated
functions, with mechanisms of action often inconsistent and
The PSPC1 protein contains a PrLD enriched in sometimes conflicting. It is plausible that the deregulation
uncharged polar amino acids, such as asparagine, glutamine, of oncogenic RNAs affects condensate function. MALAT1
and tyrosine. Glycine is also abundant and contributes to is recruited to speckles through direct interactions with
the liquid–gel phase separation properties of PSPC1. The multiple splicing-associated proteins; however, it is not
PrLD domain contributes to the phase separation ability of strictly required for speckle formation. MALAT1,
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PSPC1. Immunofluorescence assays have detected PSPC1 also known as NEAT2, is an ~8 kb highly abundant
in mouse oocytes at the germinal vesicle (GV) stage. ncRNA conserved across vertebrates and considered an
PSPC1 knockdown resulted in the blocking of oocyte oncogene. Using capture hybridization analysis of RNA
maturation in vitro. Checkpoint kinase 1 (CHK1) is vital targets, researchers demonstrated MALAT1 binding to
during the GV stage of mouse oocytes. PSPC1 interacts active genes, suggesting that both NEAT1 and MALAT1
with the serine/threonine protein phosphatase PPP5C, contribute structurally to the organization of nuclear
which regulates CHK1 phosphorylation. 138 bodies at heavily transcribed sites. Engreitz et al.
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PSPC1 also functions as an activator of transcription employed RNA–RNA interaction assays (RAP-RNA) and
factors involved in epithelial-to-mesenchymal transition showed that MALAT1 localizes to actively transcribed

Volume 3 Issue 4 (2024) 9 doi: 10.36922/td.4657