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Microbes & Immunity The feature of bladder cancer stem cells

Figure 5. The Notch pathway. Notch ligand binds to the Notch receptor at the site of a repeated sequence of epidermal growth factor (green section).
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Cleavage of the Notch receptor is catalyzed by ADAM and γ-secretase enzymes. This cleavage releases the Notch Intracellular Domain (NICD), which then
translocates to the nucleus. Once in the nucleus, NICD interacts with the coactivator Mastermind (MAM) and CBF1/Suppressor of Hairless/LAG1 (CSL)
complex, thereby promoting gene transcription.

CSL serves as a transcription factor in the classical In addition, our investigations identified that GATA3
Notch pathway. Hayashi et al. at the Vancouver Prostate effectively binds to the −1710 – −1530 bp region of the STAT3
Centre in Canada revealed that the Notch2 overexpression promoter, subsequently suppressing its transcription as
group exhibited larger tumors and upregulated expression confirmed through chromatin immunoprecipitation (ChIP)
of EMT-related proteins through experiments conducted and qRT-PCR. Overexpression of GATA3 in BCSCs resulted
in mice. Mechanically, NICD, derived from Notch2, in an 86% reduction in the number of spheroids and a 68%
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translocates into the cell nucleus, where it interacts reduction in the percentage of CD44 cells, indicative of its
+
with CSL and finally regulates the transcription levels of suppressive function in the self-renewal of BCSCs. Further
downstream genes (HES and HEY), thereby significantly exploration revealed that the H3K9me3 modification
increasing cell proliferation and invasion. Taken together, mediated by KMT1A in the −1351 – −1172 bp region of
Notch2 activates the Notch signaling pathway through the GATA3 promoter inhibited GATA3 transcription while
CSL in BC cells, thereby driving the progression of BC. upregulating STAT3 expression, thus driving the self-
renewal of BCSCs. In summary, the KMT1A-GATA3-
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3.3.4. KMT1A-GATA3-STAT3 pathway STAT3 pathway represents a novel self-renewal signaling
KMT1A encodes an evolutionarily conserved histone pathway that drives the self-renewal of BCSCs.
methyltransferase responsible for catalyzing the
trimethylation of lysine 9 on histone H3 (H3K9me3), a 3.3.5. Hippo pathway
process crucial for heterochromatin formation and gene In the Hippo pathway, the mammalian Ste20-like kinases
silencing (Figure 6). Through transcriptome microarray 1/2 (MST1/2) and large tumor suppressor 1/2 (LATS1/2)
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analysis of human BCSCs (BCMab1 CD44 ) and BCNSCs phosphorylate YAP/TAZ in the cytoplasm. When YAP/
+
+
(BCMab1 CD44 ), our group observed that the expression TAZ remains unphosphorylated, they translocate into
-
-
of KMT1A in BCSCs was at least three times higher than the cell nucleus and act as transcriptional coactivators,
that in BCNSCs. Consequently, KMT1A was established as thereby activating the TEA domain (TEAD) transcription
the first specific marker for BCSCs, holding vast potential factor (Figure 7). This activation of TEAD leads to the
for targeted therapy in the realm of BCSC treatment. upregulation of target gene expression, subsequently
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Volume 1 Issue 1 (2024) 34 doi: 10.36922/mi.2377