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Page 2 of 14 Santoni et al. J Cancer Metastasis Treat 2020;6:22 I http://dx.doi.org/10.20517/2394-4722.2020.49

INTRODUCTION
According to the World Health Organization (WHO) classification, Glioblastoma multiforme (GBM)
is a grade IV malignant glial tumor which displays astrocytic differentiation. It is considered one of
[1]
the most common malignant primary intracranial tumors . Despite treatment with a combination of
[2]
surgery, chemotherapy and radiotherapy, GBM patients have poor prognosis . In 1940, the terms primary
glioblastoma (pGBM) and secondary glioblastoma (sGBM) were first used by Scherer to distinguish
[3]
between rapidly progressing de novo tumors and tumors derived from a pre-existing astrocytoma .
[3]
According to Scherer , pGBM and sGBM display the same histomorphological hallmarks, while differing
in biological properties such as type of evolution, clinical manifestation and progression. The differences
among primary and secondary GBM arise at the genotypic and epigenetic levels. It is currently widely
accepted that the occurrence, progression and even recurrence of both pGBM and sGBM, depend on
the accumulation of mutations in neural stem cells, which undergo transformation into glioma cancer
stem cells (GSCs). GSCs are characterized by self-renewal and asymmetric cell division, thus allowing
[4]
the production of proliferating progenitor cells with stem cell features and differentiated cancer cells .
Importantly, GSCs are more resistant to radio- and chemotherapy respect to the proliferative progenitors
Cip1
present in the tumor. The p21 pathway plays an important role in the maintenance of the GSC pool
Cip1
because it induces a quiescent state that prevents hyperproliferation and exhaustion. p21 is involved in
cell cycle arrest which occurs in response to DNA damage. It stimulates DNA repair, thus reducing genetic
instability. Thus, p21 is fundamental in maintaining the GSC pool and its genomic integrity .
Cip1
[5]
As the presence of GSCs reduces the efficacy of standard therapy, there is an increased imperative to
identify new targets and therapeutic strategies in GBM patients.

CIP1
P21 : P53-DEPENDENT AND INDEPENDENT REGULATION
Cip1
KIP2
KIP1
The proteins, p21 , p27 and p57 , belong to the Cip/Kip family of cyclin dependent kinase inhibitors
(CKIs) and are found in mammals. Although p21 and p27 were initially classified as tumor suppressor
KIP1
Cip1
proteins due to their involvement in the p53-dependent cell cycle arrest, it is now evident that their roles
are more complex. Dysregulation of Cip/Kip protein may provoke specific defects in its tumor suppressor
Cip1
activity, while its oncogenic functions may be preserved, thus supporting cancer development. p21
acts as a tumor suppressor through binding and inhibiting CDK/cyclin complexes and the proliferating
[6]
Cip1
cell nuclear antigen (PCNA), thus blocking cell proliferation . However, it has been shown that p21
also displays additional functions such as stem cell pool preservation, regulation of cell migration and
Cip1
[7,8]
apoptosis . While some cancer types do not express p21 , its over-expression or cytoplasmic localization
has been associated with poor prognosis in several malignant tumors [Figure 1].
[8]
Cip1
p21, a potent cyclin-dependent kinase (CDK) inhibitor, also known as p21 /Waf1/CDKN1A, is a small
protein consisting of 165 amino acids. p21 is able to arrest the cell cycle in the G1/S and G2/M phases
by inhibiting CDK4, 6/cyclin-D and CDK2/cyclin-E, thus controlling E2F activity . The principal
[8,9]
Cip1
transcription regulator of p21 is p53. In fact, DNA damage and oxidative stress enhance p53 activity and
trigger p21 expression . In addition, under the influence of certain factors, the p21 -dependent cell
Cip1
[10]
Cip1
Cip1
cycle arrest can be also regulated in a p53-independent manner. As such, p21 can be transactivated by
the BRCA1 variants in a p53-dependent and independent manner . Additionally, transforming growth
[11]
Cip1
factor β (TGFβ) and mitogen activated protein kinase control p21 expression by phosphorylation of
[12]
Cip1
SMAD1 and SMAD3, while c-Myc over-expression abrogates TGFβ-mediated p21 /SMAD binding .
The E3 ubiquitin ligase, Makorin Ring Finger Protein-1 [a protein involved in cell cycle regulation] reduces
Cip1
p21 levels by p53 ubiquitination and direct p21 Cip1 polyubiquitination . Contrarily, Double homeobox4,
[13]
Cip1
Cip1
which enhances p21 promoter activity via the transcription factor Sp1, increases p21 expression
[14]
Cip1
levels . In addition, promoter activity and p21 transcription can be stimulated in a p53-independent