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Santoni et al. J Cancer Metastasis Treat 2020;6:22 I http://dx.doi.org/10.20517/2394-4722.2020.49 Page 3 of 14

Figure 1. Dual role of p21 Cip1 pathway in cancer

pathway via over-expression of β1-integrin receptors, and engagement of the transcription factor Sp1 and
Cip1
the P300 co-activator p21 Cip1[15] . Down-regulation of p21 mRNA expression can also be induced by c-Myc
[16]
through interactions with the initiator binding zinc finger transcription factor, MIZ-1 . Similarly, the pro-
Cip1
Cip1
myelotic zinc finger can bind to the p21 promoter, thus blocking the Sp1/p21 promoter interaction
Cip1
[17]
and reducing p21 expression . The liver kinase B1 is a serine/threonine kinase that activates AMPK and
Cip1
regulates cell growth and apoptosis by triggering a p53-dependent p21 increase [18,19] . Enhanced p21
Cip1
levels, induced by increased p53 and Sp1/DNA binding activity, have been also found in human fibroblasts
during replicative senescence [20-22] . Moreover, the alkylating agent Temozolomide (TMZ) induces G2-M cell
cycle arrest and senescence through the Mre11-Rad50-Nbs1 (MRN) complex and activation of the ATR/
CHK1 axis. TMZ-induced senescence requires a functional p53, a functional NF-κB pathway, as well as a
sustained p21Cip1 induction. Upon TMZ exposure, as a consequence of the E2F1/DP1 complex disruption,
[23]
a strong repression of the mismatch repair proteins MSH2, MSH6, EXO1 and RAD51 was observed .
The Wnt signaling pathway is a critical regulator of cancer stem cell (CSC) features and has been associated
+
+
with poor prognosis. Its downregulation is responsible for diminished numbers of CD133 CD44 CSCs [in
this regard, recent studies on colon cancer have demonstrated that the knock-down of zeste homologue 2
(EZH2), a key component of the Polycomb-Repressive Complex 2, is involved in maintaining the
transcriptional repressive state of cycle arrest and apoptosis of CSC-like cells . EZH2 expression positively
[24]
correlates with levels of Wnt/β-catenin pathway target genes. EZH2 is essential for the maintenance of
[25]
CSC-like cell properties] [Figure 2] . Several findings demonstrate that EZH2 knockdown inactivates
Cip1
[25]
the Wnt/β-catenin pathway by increasing p21 expression, resulting in G1/S-phase arrest . EZH2
knockdown in CD133 /CD44 SW480 cells has been shown to induce the increase of p21 Cip1 with
+
+
consequent reduction of β-catenin, vimentin and c-Myc expression. Moreover, the inhibition of EZH2 via
a specific inhibitor promotes enhancement of p21 expression and inactivation of the Wnt/β-catenin
Cip1
[25]
pathway .
Interestingly, the role of EZH2 in chemotherapy drug resistance has also been investigated. A decrease in
EZH2 expression was demonstrated to promote apoptosis, cell cycle arrest at the G1/S phase, and reduce
[26]
expression of multi-drug resistant proteins in TMZ-resistant GBM cells . GSC maintenance involves the
cell-division cycle protein 20 (CDC20), an activator of the E3 ubiquitination ligase complex. Silencing