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

Gatti, Veronica; Fernanda, Cláudia; Annicchiarico-Petruzzelli, Margherita; Melino, Gerry; Peschiaroli, Angelo

doi:10.1002/1878-0261.12473

Cited by 65 publications

(67 citation statements)

References 194 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%

“…The AKT/FOXM1/STMN1 pathway was indicated to drive resistance to tyrosine kinase inhibitors in advanced non-small cell lung cancer including LSCC (22). TP63 is an action target of STXBP4 (10)(11)(12). The development of STXBP4 inhibitors is considered to be key to the development of precision medicine with truly active target drugs for LSCC patients.…”

Section: Discussionmentioning

confidence: 99%

“…At present, taxane, antiangiogenesis inhibitors and immuno-checkpoint inhibitors are regarded as essential in the treatment of LSCC, the drug targets of which are TUBB3, VEGFR2, and PD-L1, respectively. Needless to say, the TP53 gene is a key factor in tumorigenesis and tumor resistance to therapy in lung cancer (5)(6)(7)(8)(9), and ΔNp63 is a putative diagnostic marker for LSCC (12). STMN1 (oncoprotein 18 and LAP18) has been suggested to be a potent predictive marker for a variety of cancers including LSCC (13)(14)(15)(16).…”

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: 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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“…TP63 gene, a p53 homolog, is a master transcriptional regulator of epithelial development and maintenance [37]. Furthermore, ∆Np63α is known as an oncogenic transcription factor in SCC [38]. Because ∆Np63α acts as the lineage-specific oncogene, the synergistic effects of IPZ and radiation were demonstrated in HNSCC cells but were not reported in human lung adenocarcinoma A549 cells, hepatocellular carcinoma HepG2 cells, or in normal human umbilical vein endothelial cells (HUVEC) ( Figure S8).…”

Section: Discussionmentioning

confidence: 99%

Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

Hazawa

Yoshino

Nakagawa

et al. 2020

Cancers

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Nuclear transport receptors, such as karyopherin-β1 (KPNB1), play important roles in the nuclear-cytoplasmic transport of macromolecules. Recent evidence indicates the involvement of nuclear transport receptors in the progression of cancer, making these receptors promising targets for the treatment of cancer. Here, we investigated the anticancer effects of KPNB1 blockage or in combination with ionizing radiation on human head and neck squamous cell carcinoma (HNSCC). HNSCC cell line SAS and Ca9-22 cells were used in this study. Importazole, an inhibitor of KPNB1, or knockdown of KPNB1 by siRNA transfection were applied for the blockage of KPNB1 functions. The roles of KPNB1 on apoptosis induction and cell surface expression levels of programmed death-ligand 1 (PD-L1) in irradiated HNSCC cells were investigated. The major findings of this study are that (i) blockage of KPNB1 specifically enhanced the radiation-induced apoptosis and radiosensitivity of HNSCC cells; (ii) importazole elevated p53-upregulated modulator of apoptosis (PUMA) expression via blocking the nuclear import of SCC-specific oncogene ΔNp63 in HNSCC cells; and (iii) blockage of KPNB1 attenuated the upregulation of cell surface PD-L1 expression on irradiated HNSCC cells. Taken together, these results suggest that co-treatment with KPNB1 blockage and ionizing radiation is a promising strategy for the treatment of HNSCC.

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“…Not surprisingly, the proliferation-inhibitory effect of ATRA and bexarotene (a pan-RXR agonist) is associated with FOXM1 downregulation [38]. How FOXM1 regulates the tightly coordinated balance between proliferation and differentiation of HNSCC cells and whether this mode of action depends on direct or indirect interactions with other transcriptional regulators of squamous differentiation such as p63 [39] or the ETS2/ELK3-AP1-SOX2-KLF5 network [40] remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

Roh

Hiou‐Feige

Misetic

et al. 2019

The Journal of Pathology

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Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three-dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated-like phenotype, indicating a context-dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC.No conflicts of interest were declared. heterogeneous expression of keratins [10][11][12].Despite a large body of evidence that FOXM1 has a role in HNSCC [13][14][15][16], its oncogenic functions in this type of cancer are not yet sufficiently understood. In Figure 3. shRNA-mediated FOXM1 knockdown decreases the number of proliferating cells and facilitates progression towards a more differentiated-like phenotype. (A) H&E staining of CAL27 organotypic cultures demonstrating a squamous-like phenotype after 16 days of culture. Scale bar = 100 μm. (B) Representative pictures of immunostaining for a series of indicated differentiation markers in CAL27 organotypic cultures at day 16. Scale bar = 100 μm. (C) RT-qPCR analysis of organotypes showing a gradual decrease in FOXM1 and its targets CCNF and GTSE1 upon FOXM1 knockdown, while differentiation-related genes such as JUND and IVL were upregulated both by FOXM1 knockdown and by increased time of culture. The data shown are from one experiment. (D) RT-qPCR analysis of FOXM1 and IVL expression levels in a large series of CAL27 shCtr or shFOXM1 organotypic cultures showing a trend for IVL upregulation following FOXM1 knockdown. Each dot represents one organotype. (E) FOXM1 expression was reduced by culturing cells in 3D organotypes as demonstrated by the reduction of FOXM1 transcript level measured by RT-qPCR. Each data point represents one sample under one condition or the other. (F) Computer-assisted quantification of the number of Ki-67-positive cells detected by immunohistochemistry in shCtr and FOXM1-depleted organotypes. Each data point represents one analyzed field of the organotype. (G) Examples for the Ki-67 immunohistochemistry data quantified in panel F. Ki-67-positive cells were detected in the basal layer for both conditions at day 8. In the control, cycling cells were present throughout the organotype at day 16, while they were restricted to the basal layer upon FOXM1 downregu...

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

Cited by 65 publications

References 194 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

Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

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