P63, A Master Regulator of Epithelial Cancer and a Squamous Cell Carcinoma Driver
Rokudai S*, Erkhem-Ochir B and Nishiyama M
Department of Molecular Pharmacology and Oncology, Graduate School of Medicine, Gunma University, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan
- *Corresponding Author:
- Rokudai S
Department of Molecular Pharmacology and Oncology
Graduate School of Medicine, Gunma University, 3-39-22 Showa
Maebashi, Gunma 371-8511, Japan
E-mail: [email protected]
Received date: August 21, 2017; Accepted date: August 31, 2017; Published date: September 07, 2017
Citation: Rokudai S, Erkhem-Ochir B, Nishiyama M (2017) P63, A Master Regulator of Epithelial Cancer and a Squamous Cell Carcinoma
Driver. Anat Physiol 7:281. doi: 10.4172/2161-0940.1000281
Copyright: © 2017 Rokudai S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution and reproduction in any medium, provided the original author and source are credited.
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TP63; TP53; PDGFRα; STXBP4; Squamous cell
Non-small cell lung cancer (NSCLC) accounts for more than 80% of
all cases of lung cancer, and is sub-classified mainly into
adenocarcinoma (AC) and squamous cell carcinoma (SCC) .
Current treatment strategies for NSCLC depend on the histological
tumor subtypes and molecular targeted agents for targetable genome
alterations. Although there have been significant advances in the
treatment of NSCLC, therapeutic improvements in the treatment of
lung SCC have lagged behind for AC, and further prognostic
progresses are needed to enable identification of SCC specific
molecules or genomic alterations that could be beneficial for
biomarkers and therapeutic targets . While several
immunohistochemical markers have been improved for their utility in
distinguishing lung SCC from lung AC, the ΔNp63 (p40) is a highly
specific marker for lung SCC [3-5].
p63, a member of the p53 family, has significant homology with p53
and regulates crucial events in the proliferative potential of epithelial
stem cells and the normal epidermal stratification development .
Alternative splicing of the TP63 gene generates transcripts encoding
two opposing functions of isoforms with the transactivation domain
(TAp63) and without the domain (ΔNp63) [7-9]. The splicing at the 3’
end of p63, resulting in the isoforms α, β and γ [7,9,10]. Early studies
showed that ΔNp63 acts as a dominant-negative transcriptional
repressor to inhibit p53- or p63-mediated transcription in vitro and in
vivo, consistent with a potential oncogenic role for the ΔNp63 isoform
[8,11]. However, the ΔNp63 isoform also has transcriptional activity
that is independent of the second transactivation domain .
Although TAp63 and ΔNp63 shows overlapping distributions in some
epithelial tissues, ΔNp63 is more expressed in basal cells, suggesting
that single expression of ΔNp63 is correlated with the cancer stem-like cell populations and that the distinct patterns of p63 isoforms may
contribute to epithelial proliferation and differentiation [13,14].
The genomic regions of the p63 gene are frequently amplified and
the levels of p63 are sometimes altered in a variety of epithelial cancers,
including lung SCC, head and neck SCC, bladder cancer, breast cancer
and cervical cancer [4,13,15,16]. Although the genomic region
containing the TP63 gene is frequently amplified in SCCs, the
expression levels of p63 are also regulated by ubiquitin-mediated
proteolysis by E3 ubiquitin ligases, such as Nedd4 , Itch ,
FBW7  and Pirh2 . The levels of ΔNp63 proteins are also
regulated in a coordinated manner by two scaffold proteins, Syntaxin
Binding Protein 4 (STXBP4) and Receptor of activated kinase C1
(RACK1), which directly interact with ΔNp63 [21,22].
Newly reported that STXBP4 plays a positive regulator of ΔNp63
stability for enhanced oncogenic potential through Platelet-Derived
Growth Factor Receptor α (PDGFRα) signaling in a ΔNp63-dependent
manner in lung SCC [21,23], although STXBP4 is originally identified
as a glucose transporter [24,25]. In line with this result, the inhibition
of the complex formation between p53 and NF-Y by gain-of-function
(GOF) of mutant p53 enhances PDGFRβ expression and promotes
metastasis in a subset of pancreatic cancers . In addition, an
interaction of p63 with mutant p53 regulates the expression of p63
target genes to enhance invasion and metastasis . Hence, the
oncogenic activity of mutant p53 may be dependent on the physical
association between p63 and mutant p53.
Despite p63, a master regulator of epithelial cells, is regulated by the
multiple signaling pathways that could contribute to several epithelial
cancers, such as the Wnt, FGFR and EGFR pathways [15,28,29], p63
expression is also reported to be decreased during progression to
invasion and metastasis, and the loss of p63 expression is associated
with poor prognosis in some cases [29-31]. It could be the balance
between the TA isotype as a tumor suppressor and ΔN isotype as an
oncogene, as well as the tissue context, which is critical for
proliferation and differentiation in both epithelial stem cells and
cancer stem cells. These issues highlight the growing importance of
accurate identification of SCC treatment for assigning patients to
appropriate histology-based therapies and the triage of tissue for
appropriate molecular studies.
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