ΔNp63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells

Holcakova, Jitka; Nekulova, Marta; Orzol, Paulina; Nenutil, Rudolf; Podhorec, Ján; Svoboda, Marek; Dvořáková, Petra; Pjechová, Mariana; Hernychová, Lenka; Vojtěšek, Bořivoj; Coates, Philip J.

doi:10.1007/s10549-017-4216-6

Cited by 22 publications

(24 citation statements)

References 54 publications

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“…At first glance this is surprising due to the previously assumed dominant negative role of this transactivation domain-lacking isoform (52). Interestingly, our report is joined by other studies demonstrating a role of deltaNp63 as a transcriptional activator (53)(54)(55)(56)(57)(58). For example, the viral oncogene protein BamHI-A rightward frame 1 (BARF1) was shown to be exclusively transactivated by deltaNp63 and not p53 or TAp63 in epithelial tumors (54).…”

Section: Discussionsupporting

confidence: 48%

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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Section: Discussionsupporting

confidence: 48%

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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“…Our own work showed that p63 controls TGF-β signaling in tumors via additional upstream miRs, thereby suppressing KSRP and miR-198 and promoting metastatic tumor dissemination, all in keeping with the wound-healing response delineated by Sundaram et al (2017) (Rodriguez Calleja et al, 2016. In addition, reciprocal regulatory interactions have been demonstrated between p63 and EGFR signaling in HNS CC and breast cancer, which provides another point of connection with the new findings (Holcakova et al, 2017). Although the involvement of SOX2 and p63 in this context may not be immedi-ately therapeutically actionable, emerging data on control of the epigenome by these central transcription factors alludes to the potential viability of future epigenetic therapy approaches for refractory HNS CC (Alexandrova et al, 2013).…”

supporting

confidence: 66%

A wound-healing program is hijacked to promote cancer metastasis

Ellisen

2017

Journal of Experimental Medicine

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“…In particular, ΔNp63α is known to regulate EMT in primary human keratinocytes and in HNC cell lines in a TGFβ-dependent manner 33 , 34 and its downregulation reduces EGFR expression in triple-negative basal-like breast cancer cells and in pancreatic cancer cells promoting cell growth and chemoresistance. 50 , 51 Thus, we showed for the first time that p63 silencing reduced EGFR expression in both HPV-positive and HPV-negative cell lines, showing also that SAHA-mediated inhibition of EGFR greatly correlates with ΔNp63α inhibition. Taken together, these data suggest that SAHA-mediated EGFR downregulation is p63-dependent.…”

Section: Discussionmentioning

confidence: 60%

“…Recently, it has been shown that silencing endogenous ΔNp63α reduces EGFR expression in triple-negative basal-like breast cancer cells and in pancreatic cancer cells promoting cell growth and chemoresistance. 50 , 51 We thus assessed EGFR expression in HPV-positive and HPV-negative HNC cell lines upon p63 knockdown. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

et al. 2019

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BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is associated with the development of head and neck cancer (HNC) and represents one of the main therapeutic targets for this disease. The use of EGFR inhibitors has limited efficacy due to their primary and acquired resistance, partially because of increased epithelial to mesenchymal transition (EMT). The HDAC inhibitor SAHA has been shown to revert EMT in different tumours, including HNC. In this study, we investigated the cooperative role of SAHA and the EGFR tyrosine kinase inhibitor gefitinib in both HPV-positive and HPV-negative HNC cell lines. METHODS: A panel of 12 HPV-positive and HPV-negative HNC cell lines were screened for cell viability upon treatment with SAHA, gefitinib and the combination of the two. Epithelial/mesenchymal marker expression, as well as activation of signalling pathway, were assessed upon SAHA treatment. ΔNp63α silencing with shRNA lentiviral particles was used to determine its role in cell proliferation, migration and TGFβ pathway activation. RESULTS: We found that both SAHA and gefitinib have antitumour activity in both HPV-positive and HPV-negative HNC cell lines and that their combination has a synergistic effect in inhibiting cell growth. SAHA treatment reverts EMT and inhibits the expression of the transcription factor ΔNp63α. Suppression of ΔNp63α reduces EGFR protein levels and decreases cell proliferation and TGFβdependent migration in both HPV-positive and HPV-negative HNC cell lines. CONCLUSIONS: Our results, by giving a clear molecular mechanism at the basis of the antitumour activity of SAHA in HNC cell lines, provide a rationale for the clinical evaluation of SAHA in combination with gefitinib in both HPV-positive and HPV-negative HNC patients. Further knowledge is key to devising additional lines of combinatorial treatment strategies for this disease.

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ΔNp63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells

Abstract: These data identify EGFR as a major target for ΔNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.

Cited by 22 publications

References 54 publications

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

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

A wound-healing program is hijacked to promote cancer metastasis

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

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