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Tumor Discovery RNA-protein complexes deregulated in cancer

NUP98-rearranged leukemia models. To restore PML The methanolic extract (RTE) from Rauvolfia
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body activity, molecules such as emodin, MLN4924, tetraphylla and its isolated compound, reserpine,
and TSA increase PML protein levels. MLN4924, an exhibit antiproliferative effects on the TNBC cell line
inhibitor of neddylation, has been shown to suppress APL MDA-MB-231. Reserpine-treated cells cease proliferation
development. Synthetic protein disaggregates, such as and undergo apoptosis through the upregulation of BAX
modified Hsp104 variants, can disaggregate condensates and MST-1 and the downregulation of Bcl2, LATS-1, and
formed by the EWS-FLI and FUS-CHOP fusion proteins. 282 YAP. Consequently, YAP levels decline, the TEAD-YAP

YB-1 represents another promising therapeutic complex fails to form, and cell growth is inhibited. 283
target, as it is involved in both P bodies and SGs. Various The transcriptional coactivators YAP and TAZ, which
approaches have demonstrated positive impacts on YB-1 interact with PDZ-binding domains, serve as downstream
inhibition. TOR kinase inhibitors, such as rapamycin, effectors of the Hippo kinase cascade. YAP/TAZ plays
also inhibit PI3K: PI3K/TOR inhibitors and suppress significant roles in cell growth, differentiation, tissue
NEAT1_2 and paraspeckles. The dual PI3K/TOR inhibitor development, and carcinogenesis. Recent studies reveal
BEZ235 reduces YB-1 expression, inhibits cancer growth, that in addition to the Hippo kinase cascade, several non-
and enhances the cytotoxicity of radiotherapy in CRC. Hippo kinases regulate YAP/TAZ signaling, influencing
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In addition, the AKT inhibitor TAS0612, which acts on tumorigenesis and progression. YAP/TAZ oncogenes also
p70S6K and p90RSK, inhibits YB-1 phosphorylation promote P body formation across various cancer cell lines.
and reverses antiestrogen resistance in BC. SU056 Mechanistically, this involves the transcriptional activation
(azopodophyllotoxin) directly binds to YB-1. Fisetin, of P body-related genes (e.g., SAMD4A, AJUBA, and WTIP)
a small molecule, inhibits the AKT–YB-1 interaction, and the suppression of the tumor suppressor gene PNRC1.
thereby preventing cancer migration in prostate tumors. Re-expression of PNRC1 or knockdown of P body core
It also reduces melanoma tumor growth in vivo through genes (e.g., DDX6, DCP1A, and LSM14A) demonstrates
a dual mechanism: inhibition of RSK kinase activity and that P bodies attenuate cell proliferation, migration, and
reduction of YB-1 protein levels. Fisetin forms a complex tumor growth induced by YAP overexpression in CRC.
with RSK2, which then binds to YB-1. Furthermore, Since P bodies act as downstream effectors of YAP/TAZ,
CX-5461 inhibits RNA polymerase I and blocks YB-1 re-expressing PNRC1 or disrupting P bodies may serve as
activity. The compound 2,4-dihydroxy-5-pyrimidinyl potential therapeutic strategies for YAP-driven tumors.
imidothiocarbomate (DPI) prevents YB-1 nuclear An additional treatment avenue involves targeting
translocation, downregulates target gene expression, and cancers with deregulated phase transitions caused by IDRs.
inhibits BC growth. Similarly, the sesquiterpene lactone For example, YK-4-279 targets the IDR of phase-separating
6-O-angeloylplenolin blocks YB-1 nuclear translocation EWS-FLI1 and blocks its interaction with RNA helicase A
and downregulates the expression of the multidrug efflux in Ewing sarcoma tumors. 280-282 Wild-type SHP2 (protein
pump MDR1 in colon cancer. tyrosine phosphatase non-receptor type 11) forms BCs in

LLPS plays a crucial role in the transcriptional response to factors such as EGF and FGF. Mutations in
programs regulated by Yes-associated protein (YAP) and SHP2 that promote BC formation drive MAPK signaling,
the transcriptional coactivator with PDZ-binding motif leading to ERK1/2 activation. Several SHP2 allosteric
(TAZ), both key components and regulators of Hippo inhibitors, including AB-3068, TNO155, RMC-4630, and
signaling. The complex formed by YAP/TAZ promotes P RLY-1971, are under clinical evaluation for solid cancers. 282
body formation in various cancer cell lines. P bodies act Advancements in permeable peptide and material
as downstream effectors of YAP/TAZ. The interaction design have also shown promise in LLPS regulation.
284
between YAP/TEAD and steroid receptor coactivator An aromatic motif-based pH-responsive hexapeptide
1 (SRC-1) is critical for the formation of SRC-1/YAP/ (VEALYL), referred to as the lysosome-targeting peptide,
TEAD condensates, which promote YAP transcription. was derived from the insulin sequence. Cancer cells
Interestingly, the anti-HIV drug elvitegravir disrupts internalize this peptide through endocytosis, triggering
SRC-1 condensates and suppresses the growth of YAP- proton-induced phase separation within lysosomes,
dependent tumors. 282 transitioning from solution to hydrogel. This hydrogelation
YAP condensates are associated with resistance to increases lysosomal volume and permeability, causing
anti-PD-1 immunotherapy. These BCs concentrate lysosomal rupture and subsequent cancer cell death.
epigenetic enzymes such as histone acetylase, making Lysosomal assemblies have been shown to enhance the
drugs targeting these enzymes potentially beneficial when efficacy of chemotherapy against multidrug-resistant cells
combined with existing therapies. in xenografted tumors. 284

Volume 3 Issue 4 (2024) 23 doi: 10.36922/td.4657