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

Rokudai, Susumu; Li, Yingchun; Otaka, Yukihiro; Fujieda, Michiru; Owens, David M.; Christiano, Angela M.; Nishiyama, Masahiko; Prives, Carol

doi:10.1073/pnas.1718546115

Cited by 27 publications

(47 citation statements)

References 48 publications

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“…The observed prognostic impact of STXBP4 and ΔNp63 con rmed previous results (10)(11)(12). We also found close relationships between VEGFR2, TUBB3, and STMN1 to patient outcome, which indicated the existence of some biological interactions between STXBP4 and these molecules.…”

Section: Stxbp4 As a Novel Therapeutic Targetsupporting

confidence: 90%

“…In this study, we con rmed the clinical prognostic impact of STXBP4 in 144 LSCC patients and rst suggested that TP63 (ΔNp63) induction might be involved in the cellular resistance mechanisms of the widely used current key drugs CDDP, TXT, and Ramucirumab. As STXBP4 has been shown to act as an up-stream regulator of TP63 (ΔNp63) (10,11), reduction in TP63 (ΔNp63) expression by STXBP4 might ameliorate tumor resistance to the current drug treatments. Additionally, IPA indicated that the action pathway of STXBP4 was independent from those of the other 4 targets examined in this study, with STXBP4, TP63 and KDR (VEGFR2) found to form a cluster independent from the other genes, TP53, TUBB3, STMN1 and CD274 (PD-L1).…”

Section: Discussionmentioning

confidence: 99%

“…We used antibodies speci c for STXBP4 (1:100 dilution; Abcam Japan, Tokyo, Japan), p53 (DO7, 1:50 dilution; Dako, Carpentaria, CA), TUBB3 (1:200 dilution; Abcam Japan, Tokyo, Japan) VEGFR2, STMN1 and PD-L1 (1:400 dilution, 1:400 dilution and 1:200 dilution; respectively; Cell Signaling Technology, Danvers, MA). Rabbit polyclonal ΔNp63 anti-body (1:100 dilution) was previously described (10,11). The reaction was visualized using the SignalStain® Boost IHC Detection Reagent (HRP, Rabbit; Cell Signaling Technology, Beverly, MA) and Histo ne Simple Stain MAX-PO (Multi) Kit (Nichirei, Tokyo, Japan) according to the manufacturers' instructions.…”

Section: Immuno-histochemical Stainingmentioning

confidence: 99%

“…We recently found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in LSCC growth through regulation of ΔNp63 (an isoform of tumor protein 63, TP63) ubiquitination and is an independent prognostic factor signifying a worse outcome in LSCC patients (10,11). ΔNp63 is an isoform of TP63, a member of the TP53 family, and its expression is widely used as a highly speci c diagnostic marker for LSCC.…”

Section: Introductionmentioning

confidence: 99%

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Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study

Erkhem-Ochir

Kaira²,

Kawabata‐Iwakawa

et al. 2020

Preprint

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Abstract Background Lung squamous cell carcinoma (LSCC) remains a challenging disease to treat, and further improvements in prognosis are dependent upon the identification of LSCC-specific therapeutic biomarkers and/or targets. We previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in lesion growth and, therefore, clinical outcomes in LSCC patients through regulation of tumor protein p63 (TP63) ubiquitination. Methods To clarify the potential of STXBP4 as a novel therapeutic target and/or a predictive biomarker of therapeutic response, we assessed its prognostic impact of the protein in 144 LSCC patients and examined whether its action pathway is distinct from those of currently used drugs in in vitro experiments including RNA-seq analysis through comparison with the other putative exploratory targets and/or markers. Results Kaplan–Meier analysis revealed that, along with ΔNp63 (an isoform of TP63) and vascular endothelial growth factor receptor 2 (VEGFR2), STXBP4 expression signified a worse prognosis in LSCC patients, both in terms of overall survival (OS, P = 0.002) and disease-free survival (DFS, P = 0.041). Multivariate analysis demonstrated STXBP4 to be an independent prognostic factor for poor DFS, while VEGFR2 (P < 0.001) and TP63 (ΔNp63, P < 0.05) were independent prognostic factors for poor OS. The action pathway of STXBP4 on suppression of TP63 (ΔNp63), which results in the and inhibits tumor growth, was unique: Ingenuity pathway analysis using the knowledge database and our RNA-seq analysis in human LSCC cell lines indicated that 35 pathways were activated or inactivated in association with STXBP4, but the action pathway of STXBP4 was distinct from those of other current drug targets: STXBP4, TP63 and KDR (VEGFR2 gene) formed a cluster independent from other target genes of tumor protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) and cluster of differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 itself appeared not to be a potent predictive marker of individual drug response, but we found that TP63, main action target of STXBP4, might be involved in drug resistance mechanisms of LSCC. Conclusion STXBP4 could afford a unique therapeutic target and a key to the development of precision medicine for LSCC patients.

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Section: Stxbp4 As a Novel Therapeutic Targetsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Immuno-histochemical Stainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study

Erkhem-Ochir

Kaira²,

Kawabata‐Iwakawa

et al. 2020

Preprint

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“…In detail, a DNp63 mutant refractory to APC/C activity increases keratinocyte proliferation, inhibits differentiation and has oncogenic activity in xenograft tumour transplantation assays. More importantly, high levels of STXBP4, a factor counteracting APC/C-mediated ubiquitination of DNp63, significantly correlate with the accumulation of DNp63 in skin and lung SCC (Rokudai et al, 2018). However, this correlation might also result from the inhibitory effect exerted by STXBP4 on diverse DNp63 targeting E3 ligases, such as ITCH and RACK1 (Li et al, 2009).…”

Section: Deregulation Of Factors Controlling Dnp63 Levels and Activitmentioning

confidence: 99%

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

Gatti

Fernanda

Annicchiarico-Petruzzelli

et al. 2019

Molecular Oncology

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Squamous cell carcinoma ( SCC ) is a treatment‐refractory tumour which arises from the epithelium of diverse anatomical sites such as oesophagus, head and neck, lung and skin. Accumulating evidence has revealed a number of genomic, clinical and molecular features commonly observed in SCC of distinct origins. Some of these genetic events culminate in fostering the activity of ΔNp63, a potent oncogene which exerts its pro‐tumourigenic effects by regulating specific transcriptional programmes to sustain malignant cell proliferation and survival. In this review, we will describe the genetic and epigenetic determinants underlying ΔNp63 oncogenic activities in SCC , and discuss some relevant transcriptional effectors of ΔNp63, emphasizing their impact in modulating the crosstalk between tumour cells and tumour microenvironment ( TME ).

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The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

Cited by 27 publications

References 48 publications

Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study

Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

The foggy world(s) of p63 isoform regulation in normal cells and cancer

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