Elevated expression of ΔNp63 in advanced esophageal squamous cell carcinoma

Kumakura, Yuji; Rokudai, Susumu; Iijima, Misaki; Altan, Bolag; Yoshida, Tatsushi; Bao, Halin; Yokobori, Takehiko; Sakai, Makoto; Sohda, Makoto; Miyazaki, Tatsuya; Nishiyama, Masahiko; Kuwano, Hiroyuki

doi:10.1111/cas.13394

Cited by 14 publications

(16 citation statements)

References 38 publications

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“…7H). In line with our previous report using lung SCC specimens (24), higher levels of Stxbp4 expression were significantly correlated with the accumulation of ΔNp63 (23,34) and with prognosis according to the combined lung SCC dataset from The Cancer Gene Atlas (SI Appendix, Fig. S9) (35).…”

Section: δNp63α Protein Is Regulated By the Apc/c During The Cell Cycsupporting

confidence: 88%

“…Purification of the doubly tagged ΔNp63α complex and MALDI-TOF mass analysis and immunohistochemical analysis were as previously described (48,49). Immunohistochemistry and scoring methods were as previously described (24,34). Details of extended methods used in this paper including cell culture, antisense oligonucleotides, baculovirus protein purification, cell synchronization, FACS analysis, far-Western immunoblotting, in vitro ubiquitination assay, in vitro degradation assay, immunofluorescence, immunohistochemistry, real-time qPCR, 3D organotypic raft cultures, anchorage-independent growth assay, and s.c. transplantation in mice are described in SI Appendix, SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

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STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis

Rokudai

Otaka

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Levels of the N-terminally truncated isoform of p63 (ΔN p63), well documented to play a pivotal role in basal epidermal gene expression and epithelial maintenance, need to be strictly regulated. We demonstrate here that the anaphase-promoting complex/cyclosome (APC/C) complex plays an essential role in the ubiquitin-mediated turnover of ΔNp63α through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ΔNp63, can suppress the APC/C-mediated proteolysis of ΔNp63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of ΔNp63α (RL7-ΔNp63α) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-ΔNp63α variant and Stxbp4 have oncogenic activity in soft agar and xenograft tumor assays. Notably as well, higher levels of Stxbp4 expression are correlated with the accumulation of ΔNp63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of ΔNp63α and may provide a relevant therapeutic target for SCC.

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Section: δNp63α Protein Is Regulated By the Apc/c During The Cell Cycsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis

Rokudai

Otaka

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…DeltaNp63 was reported to play a crucial role in keratinocyte differentiation and its expression was shown to be a defining feature of basal cells and squamous cell carcinomas (12)(13)(14). Concordantly, deltaNp63 is expressed in many squamous-like cancers, including esophageal squamous cell carcinoma (15,16), head and neck squamous carcinoma (17), and lung squamous cell carcinoma (18,19). p63 was found to drive epidermal differentiation through distal regulatory elements associated with its target genes (20).…”

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confidence: 98%

DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network

Hamdan

Johnsen

2018

Proc. Natl. Acad. Sci. U.S.A.

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Molecular subtyping of cancer offers tremendous promise for the optimization of a precision oncology approach to anticancer therapy. Recent advances in pancreatic cancer research uncovered various molecular subtypes with tumors expressing a squamous/basal-like gene expression signature displaying a worse prognosis. Through unbiased epigenome mapping, we identified deltaNp63 as a major driver of a gene signature in pancreatic cancer cell lines, which we report to faithfully represent the highly aggressive pancreatic squamous subtype observed in vivo, and display the specific epigenetic marking of genes associated with decreased survival. Importantly, depletion of deltaNp63 in these systems significantly decreased cell proliferation and gene expression patterns associated with a squamous subtype and transcriptionally mimicked a subtype switch. Using genomic localization data of deltaNp63 in pancreatic cancer cell lines coupled with epigenome mapping data from patient-derived xenografts, we uncovered that deltaNp63 mainly exerts its effects by activating subtype-specific super enhancers. Furthermore, we identified a group of 45 subtype-specific super enhancers that are associated with poorer prognosis and are highly dependent on deltaNp63. Genes associated with these enhancers included a network of transcription factors, including HIF1A, BHLHE40, and RXRA, which form a highly intertwined transcriptional regulatory network with deltaNp63 to further activate downstream genes associated with poor survival.

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“…ΔNp63 in breast and esophageal squamous carcinoma was previously reported to act as an activator of cell migration and invasion [ 30 , 31 ]. ΔNp63 was also highly expressed in several cancer tissues such as esophageal squamous cell carcinoma and cervical cancer with poor prognosis [ 22 , 32 ]. Similarly, our results also demonstrated that ΔNp63 induces apoptosis and activates migration and invasion in cervical cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Synergetic Effects of Intronic Mature miR-944 and ΔNp63 Isoforms on Tumorigenesis in a Cervical Cancer Cell Line

Kim

Park

Chang

et al. 2020

IJMS

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miR-944 is located in an intron of the tumor protein p63 gene (TP63). miR-944 expression levels in cervical cancer tissues are significantly higher than in normal tissues and are associated with tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and survival. However, associations of miR-944 with its host gene, TP63, which encodes TAp63 and ΔNp63, in cervical cancer have not been fully investigated. A positive correlation between miR-944 and ΔNp63 mRNA expression was identified in cervical cancer tissues. Furthermore, when the expression of miR-944 and ΔNp63 was simultaneously inhibited, cell proliferation-, differentiation- epithelial–mesenchymal transition (EMT)-, transcription-, and virus-associated gene clusters were shown to be significantly more active according to functional annotation analysis. Cell viability and migration were more reduced upon simultaneous inhibition with anti-miR-944 or ΔNp63 siRNA than with inhibition with anti-miR-944 or ΔNp63 siRNA alone, or scramble. In addition, Western blot analysis showed that the simultaneous inhibition of miR-944 and ΔNp63 reduced EMT by increasing the expression of epithelial markers such as claudin and by decreasing mesenchymal markers such as N-cadherin and vimentin. Slug, an EMT transcription factor, was also decreased by the simultaneous inhibition of miR-944 and ΔNp63. Thus, associations between miR-944 and ΔNp63 in cervical cancer could help to elucidate the function of this intronic microRNA and its role in carcinogenesis.

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Elevated expression of ΔNp63 in advanced esophageal squamous cell carcinoma

Cited by 14 publications

References 38 publications

STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis

STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis

DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network

Synergetic Effects of Intronic Mature miR-944 and ΔNp63 Isoforms on Tumorigenesis in a Cervical Cancer Cell Line

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