Page 8 - Read Online

Page 4 of 14 Santoni et al. J Cancer Metastasis Treat 2020;6:22 I http://dx.doi.org/10.20517/2394-4722.2020.49

Figure 2. EZH2/WNT/p21 Cip1 pathway in cancer stem cells [24]

CDC20 expression attenuates GSC proliferation, self-renewal and in vivo tumor growth by inducing
Cip1
apoptosis and cell cycle inhibition. CDC20 maintains the GSC phenotype through p21 degradation.
Cip1
[27]
CDC20 inhibition stabilizes p21 and represses Survivin, CDC25C and c-Myc survival gene expression .
Cip1
In addition, the roles of p21 and p27 KIP1 in GSCs treated with camptothecin [CPT, a specific inhibitor
of the DNA topoisomerase I that induces DNA double-strand breaks in GSCs carrying the homozygous
Cip1
CDKN2A/ARF deletion] have recently been investigated . The results showed that both p21 and
[28]
KIP1
p27 proteins block the cell cycle in both unstressed conditions and in response to genotoxic stress. Cip/
Kips expression was upregulated after CPT treatment, with a peculiarly nuclear localization. CKIs protect
cancer cells against CPT damage by stopping cell cycle progression. Notably, cells become more susceptible
Cip1
KIP1
to DNA damage in the absence of p21 and p27 proteins, leading to impaired cell cycle blockage under
KIP1
Cip1
genotoxic stress. Overall, the existing literature demonstrates that p21 and p27 may act both as tumor
suppressors by reducing cell proliferation, and as oncogenes, by increasing cellular resistance in response
to DNA damage. A deeper understanding of Cip/Kip functions may be relevant and useful to improve
understanding on the mechanisms underlying the acquisition of chemoresistance in cancer .
[28]
Finally, p21 Cip1 is one of the major regulators of cell cycle and has been previously linked to apoptosis
[29]
resistance in glioma cells . O(6)-Methylguanine-DNA methyltransferase (MGMT) plays a major role
in the resistance to alkylating agents in gliomas . Happold et al. demonstrated that in TMZ-resistant
[30]
[31]
glioma cell line, constitutively expressing MGMT, but not in glioma cell lines negative for MGMT, a strong
Cip1
up-regulation of MGMT levels and elevated p21 mRNA levels and slower cell cycle progression ;
[31]
Cip1
however, silencing p21 silencing in resistant vs. normal glioma cells does not evidenced major changes
[32]
Cip1
in cell cycle distribution. Mostofa et al. clarified the role for p21 in TMZ-resistance in glioma cells-the
Cip1
p21 protein sequestrates PCNA by binding to it during the cell cycle, thus attenuating DNA replication.
In human GBM, MGMT harbors a PCNA-interacting protein motif (PIP box), thus associating with PCNA
Cip1
Cip1
and in turn, p21 . PCNA is strictly controlled by p21 , a strong binder and sequestrator of the former.
Alkylating DNA damage induces MGMT and PCNA colocalization, and this occurs mainly in glioma cells
Cip1
Cip1
deficient in p21 , as p21 expression directly correlates with higher MGMT mRNA and protein levels,
Cip1
higher MGMT activity and greater resistance to alkylating agents. p21 strongly disrupts MGMT-PCNA
complexes within glioma cells. MGMT proteins are downregulated at mid to late S-phase and specifically
Cdt2
depredated by the PCNA-dependent ubiquitin-ligase, CRL4 .