SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M.; Pedamallu, Chandra Sekhar; DeLuca, David S.; Brooks, Angela N.; Wang, Su; Que, Jianwen; Rustgi, Anil K.; Wong, Kwok-Kin; Ligon, Keith L.; Liu, X. Shirley; Marto, Jarrod A.; Meyerson, Matthew; Bass, Adam J.

doi:10.1172/jci71545

Cited by 145 publications

(166 citation statements)

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“…Studies in squamous carcinoma cell lines have demonstrated that SOX2 and ΔNp63 proteins interact physically and cooperate functionally to co-regulate scores of downstream target genes. 34 We found that exposure to NO, in addition to reducing SOX2 expression, also decreased mRNA expression of both the TA and ΔN isoforms of p63 in oesophageal squamous cells.…”

Section: Discussionmentioning

confidence: 63%

“…22, 34 The p63 gene encodes two major protein isoforms, TAp63 and ΔNp63, and p63 gene expression normally is linked with that of SOX2 in the oesophagus. To determine whether NOC-9 decreases p63 as well as SOX2, we determined mRNA expression for p63 isoforms using qRT-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…22, 34, 47 Embryonic p63-knockout mice develop an oesophagus lined by columnar cells. 48 The p63 gene encodes two major, functionally-distinctive protein isoforms, TAp63 and ΔNp63.…”

Section: Discussionmentioning

confidence: 99%

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In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression

Asanuma

Huo

Agoston

et al. 2015

Gut

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Objective Barrett’s metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, GORD patients also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. Design Oesophageal squamous cells from Barrett’s patients were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor), and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by Western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically-induced GORD fed diets with and without nitrite supplementation. Results In oesophageal squamous cells, NO profoundly decreased SOX2 protein, and caused a significantly greater decrease in SOX2 mRNA than acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed normal diets. Conclusion In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett’s pathogenesis.

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Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

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In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression

Asanuma

Huo

Agoston

et al. 2015

Gut

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“…Another example of an amplified lineage-survival oncogene in SCC is the high mobility group transcription factor SOX2 [14]. Interestingly, ΔNp63α and Sox2 were shown to cooperatively regulate gene expression essential for SOX2-amplified SCC growth and survival [15]. Whether the increased SCC development in our transgenic ΔNp63α overexpressing mouse model is dependent on cross-talk between ΔNp63α and Sox2 is currently not clear.…”

mentioning

confidence: 88%

ΔNp63α Acts as a Lineage-Survival Oncogene in Squamous Cell Carcinoma

Devos¹,

Declercq²

2017

J Med Surg Pathol

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CommentaryThe transcription factor p63 is a p53 family member involved in numerous biological processes, including ectodermal development, skin homeostasis, female germline protection and carcinogenesis. Of the multiple isoforms found in higher vertebrates, ΔNp63α is the predominant one expressed in the epidermis. Lacking the N-terminal, but containing the C-terminal transactivation domain, ΔNp63α has both transcriptional repressor and transactivation properties, positively and negatively regulating a plethora of genes, involved in proliferation, stemness, cell death, inflammation and differentiation [1].Two decades following the discovery of TP63, ΔNp63α has been proven to be a crucial player in Squamous Cell Carcinoma (SCC) development and treatment. Particularly because the majority of SCCs overexpress ΔNp63α, often as a result of amplification of the TP63 genomic region [2,3]. In agreement, numerous in vitro studies highlight ΔNp63α as a potential oncogene, due to its ability to bypass oncogene-induced senescence, inhibit apoptosis or induce angiogenesis. On the other hand, observations in patients and genetic mouse models with single-allelic loss of p63 reveal an inverse correlation between ΔNp63α levels and tumor invasiveness and metastasis [2,3]. In addition, tumor ΔNp63α levels were shown to correlate both with better or worse therapeutic responses, adding additional complexity on the diverse regulatory actions of ΔNp63α [3]. However, it is clear that, depending on the stage of the tumor and the type of tissue, ΔNp63α is able to affect tumorigenesis in diverse ways. Over the years, the crucial role of ΔNp63α during development and homeostasis has prompted the generation of transgenic mouse models capable of studying the influence of ΔNp63α during the different stages of carcinogenesis. Previously reported ΔNp63α transgenic mice succumb to spontaneous inflammation early in life, preventing the use of long-term cancer models [4].In a study recently published in the Journal of Investigative Dermatology, we reported a Keratin 5-Cre-recombinase-controlled ROSA26 promoter-based transgenic ΔNp63α mouse model [5]. We demonstrated that these epidermal ΔNp63α-overexpressing mice develop only mild spontaneous phenotypes: epidermal hyperplasia, which gets milder with age, minor hair defects and occasional epidermal cyst development, but no spontaneous inflammation. We explain this difference with the transgenic mice developed by Romano and colleagues by the moderate ΔNp63α overexpression levels in our model due to the relatively weak ROSA26 promoter, avoiding drastic developmental and inflammatory phenotypes. This allowed us to apply the 7,12-dimethylbenz[a]anthracene (DMBA)-based carcinogenesis model and found that ΔNp63α-overexpressing mice developed SCCs much faster and in greater numbers compared to wild-type littermates. No significant differences in DMBA-induced cytotoxicity were observed between transgenic and wild-type epidermis. Instead, isolated keratinocytes from ΔNp63α-overexpressing mice showed a delay ...

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“…Review of public databases and the published UBTC transcriptome do not support this hypothesis. On the other hand, there is evidence that p63, jointly with Sox2, regulates the Ret target ETV4 gene (36). Since p63 expression is ini- tiated later than Ret in the developing kidney, it is still possible that GDNF/Ret or other tyrosine kinases may be upstream of p63.…”

Section: Although Occasional Ubtcmentioning

confidence: 99%