Spatiotemporal Regulation of ΔNp63 by TGFβ-Regulated miRNAs Is Essential for Cancer Metastasis

Bui, Ngoc H.B.; Napoli, Marco; Davis, Andrew John; Abbas, Hussein A.; Rajapakshe, Kimal; Coarfa, Cristian; Flores, Elsa R.

doi:10.1158/0008-5472.can-19-2733

Cited by 25 publications

(22 citation statements)

References 63 publications

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“…Those data are opposite to previous findings where mutant p53 inhibited p63 only in the presence of TGFβ, through the formation of a mutant p53/Smad/p63 complex [163]. Alternatively, TGFβ may inhibit ΔNp63 through Smad3, which induces ΔNp63‐targeting miRNAs [164]. There is also evidence for a stimulatory role of BMP4/SMAD signalling on ΔNp63 in normal epithelium [165,166].…”

Section: Signalling Pathways That Regulate P63 Levels or Activitycontrasting

confidence: 70%

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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Section: Signalling Pathways That Regulate P63 Levels or Activitycontrasting

confidence: 70%

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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“…Importantly, restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell migration, and tumor metastasis. Notably, it is also reported that activation of TGF-β can inhibit ΔNp63α expression through the Smad-mediated up-regulation of several miRNAs [ 48 ]. Therefore, it appears that TGF-β can regulate ΔNp63α expression at multiple levels, including antagonized p63 transactivation function by mutant p53-Smads interplay, transcriptional suppression of p63, posttranscriptional regulation via miRNAs, or reduced protein stability as shown in this study.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis

Niu

et al. 2021

PLoS Biol

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Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-β receptor I (TβRI), FBXO3, and p63 protein expression and that high expression of TβRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-β signaling in promoting tumor metastasis and that the TβRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.

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“…For instance, in basal-like breast cancer, leader cells showed high motility, co-expressed epithelial (miR-205) and mesenchymal (ZEB2) expression, and retained cell-cell adhesion. This ‘partial EMT’ program was driven by ΔNP63α [ 143 ], which was found to be a “phenotypic stability factor” for hybrid E/M phenotype [ 83 ] and a downstream target of TGF-β signaling [ 144 ]. In luminal breast cancer, the leader cells exhibited molecular signatures of partial EMT and collective invasion, and were able to switch back and forth to a follower cell phenotype during collective migration.…”

Section: Role Of Partial Emt In Collective Migrationmentioning

confidence: 99%

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

Saxena

Jolly

Balamurugan

2020

Translational Oncology

150

112

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Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.

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Spatiotemporal Regulation of ΔNp63 by TGFβ-Regulated miRNAs Is Essential for Cancer Metastasis

Cited by 25 publications

References 63 publications

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

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

Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

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