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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 9 of 14

accelerated cell cycle progression and repressed apoptosis. SNHG3 facilitated the malignant progression
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of glioma through epigenetically repressing KLF2 and p21 via recruitment of the enhancer of zeste
homolog 2 to the promoter of KLF2 and p21 Cip1[60] . Similarly, overexpression of SNHG6 promotes the
malignant phenotype, while loss-of-function revealed that the silencing of SNHG6 inhibits glioma cell
[61]
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growth in a p21 -dependent manner .
The LncRNA PTEN pseudogene-1 (PTENP1) has been described to be involved in the development and
progression of several cancers. However, little is known about the molecular mechanism by which lncRNA
PTENP1 affects the development and progression of gliomas. Overexpression of PTENP1 suppressed
SHG44 expression as well as U251 cell proliferation, invasion and migration by inducing p21 expression
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[62]
while inhibiting p38 signaling .
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Among LincRNA, the LincRNA-p21 is an intergenic LncRNA which resides on the chromosome 17,
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upstream of the p21 gene. It was identified ten years ago as being one of the eleven LincRNAs that are
[63]
increased in expression in response to p-53 induced DNA damage .
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LincRNA-p21 is the downstream target of p53 and controls the cell cycle, damage of DNA and its repair
process . The LincRNA-p21 suppresses the p53-dependent transcription activity and affects p53-repressed
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[63]
genes. It is required to trigger p53-dependent apoptosis of DNA damaged cells through physical association
with the ribonucleoprotein K (hnRNP-K) .
[64]
LincRNA-p21 also regulates the G1/S checkpoint of the cell cycle by modulating the expression of
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its neighboring gene p21 Cip1[65] and mediating radiation-induced apoptosis [66,67] . LincRNA-p21 Cip1 is a
[68]
potent suppressor of GSC and works by triggering apoptosis through the NOXA pro-apoptotic gene .
It negatively regulates β-catenin activity in GSCs. Downregulation of LincRNA-p21 Cip1 in GSCs results
in upregulation of Hu antigen R (HuR), and this is caused by miR-146b-5p down-regulation. Moreover,
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knockout of LincRNA-p21 or HuR was shown to increase GSC β-catenin expression, stemness and GSCs
radioresistance . Previous findings also showed that LincRNA-p21 is a hypoxia-responsive lncRNA
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[51]
able to regulate the cell cycle and apoptosis. It has also been shown to be responsible for the Warburg effect
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in cervical cancer. Although hypoxia was found to increase LincRNA-p21 expression in U251MG glioma
cell line, its functions in hypoxic glioma remain unknown. Knockdown of LincRNA-p21 induced G2/M
phase arrest, promoted apoptosis, decreased cell proliferation and motility, and also reduced autophagy
[69]
through the HIF-1/Akt/mTOR/P70S6K pathway . These findings are suggestive of a mechanism by which
LincRNA-p21 enhances the radiosensitivity of hypoxic tumor cells.
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The antisense FAM83H RNA1 (FAM83H-AS1) is known to be upregulated in glioma. Silencing of
FAM83H-AS1 suppressed glioma proliferation and apoptosis. FAM83H-AS1 inhibits CDKN1A expression
[70]
by recruiting EZH2 to the promoter of CDKN1A, thereby influencing cell cycle and proliferation .
LincRNAs also regulates cellular senescence. Thus, LincRNA-ASEN, which is expressed in prematurely
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senescent cells, has been shown to repress cellular senescence by reducing p21 expression, both during
and post-transcription. The complex formed by the interaction between Linc-ASEN and UPF1 can
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suppress p21 transcription through the recruitment of Polycomb Repressive Complex 1 and 2 (PRC1
and PRC2) to the p21 locus. This prevents binding of the transcriptional activator p53 to the p21 promoter
[64]
through histone modification .
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CLINICAL ROLE OF MIRNA TARGETING P21 AND LNCRNA-P21 IN GLIOMAS
The identification of glioma-related biomarkers is an urgent necessity as it would enable the development
of new therapeutic approaches, while improving the ability to predict responsiveness to chemo- and