p63 at the Crossroads between Stemness and Metastasis in Breast Cancer

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

doi:10.3390/ijms20112683

Cited by 50 publications

(41 citation statements)

References 121 publications

(150 reference statements)

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“…The p63 family members are crucial regulators of cancer and have been found to play an important role in embryonic stem cells [25][26][27] . As reported by several studies, TAp63 suppressed the progression of cancers, and thus be considered as a promising strategy for therapeutics 9,10,28 .…”

Section: Discussionmentioning

confidence: 99%

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

et al. 2020

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Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

et al. 2020

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“…p63 is critical for EGFR-, JUN/FOS-and TGFβ/SMADmediated invasion and gene activation p63 has recently been shown to control epithelial stemness and cell fate specification [34], and its expression has been linked to basal-like breast cancers in correlation with additional basal epithelial markers [33]. Previous work by us and others showed that signaling by EGFR and its ligand HB-EGF can be controlled by p63-and/or JUN-mediated activation of the EGFR and HB-EGF genes [35,39,40].…”

Section: Egfr Signaling Enables and Potentiates Tgfβ Induction Of Ap-mentioning

confidence: 99%

“…TAp63 and ΔNp63 isoforms can have dual, genespecific but opposite, effects on target genes [33], implying that their expression needs to be finely regulated during cancer initiation and progression. ΔNp63 isoform is frequently overexpressed in human malignancies and can regulate oncogenic routes involved in the pathogenesis of breast carcinoma by contributing to proliferation, stemness and survival of breast tumors [34]. Previously, we demonstrated, on a genome-wide scale, that co-activation of RAS and TGFβ signaling via downregulation of mutant p53 can enhance binding of p63 to its genomic sites [35].…”

Section: Introductionmentioning

confidence: 97%

TGFβ and EGF signaling orchestrates the AP-1- and p63 transcriptional regulation of breast cancer invasiveness

et al. 2020

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Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-β (TGFβ)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGFβ critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ΔN isoform of transcriptional regulator p63. EGFR and ΔNp63 enabled and/or potentiated the activation of a subset of TGFβ-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGFβ-and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGFβ induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGFβ-induced gene activation after p63 depletion. p63 is also involved in the transcriptional regulation of heparin binding (HB)-EGF and EGFR genes, thereby establishing a self-amplification loop that facilitates and empowers the pro-invasive functions of TGFβ. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGFβ were efficiently inhibited by clinically relevant chemical inhibitors. Our findings may, therefore, be of importance for therapy of patients with breast cancers with an activated EGFR-RAS-RAF pathway.

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“…It has been also found that FBXW7 targets ΔNp63 for polyubiquitination and subsequent degradation. ΔNp63 is highly expressed in the majority of SCC where it acts as an oncogene by regulating specific transcriptional programs aimed to sustain malignant cell proliferation, stemness and survival [ 116 , 117 , 118 , 119 , 120 ]. In a large panel of human cancer cell lines and patient biopsies, FBXW7 abundance was positively correlated with sensitivity to HDAC inhibitors (HDACi), which are known to downregulate ΔNp63 through FBXW7 to induce a tumor-suppressive program [ 121 ].…”

Section: Crls and Scc Etiologymentioning

confidence: 99%

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

Gatti

Bernassola

Talora

et al. 2020

Cancers

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The ubiquitin system is a dynamic regulatory pathway controlling the activity, subcellular localization and stability of a myriad of cellular proteins, which in turn affects cellular homeostasis through the regulation of a variety of signaling cascades. Aberrant activity of key components of the ubiquitin system has been functionally linked with numerous human diseases including the initiation and progression of human tumors. In this review, we will contextualize the importance of the two main components of the ubiquitin system, the E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), in the etiology of squamous cell carcinomas (SCCs). We will discuss the signaling pathways regulated by these enzymes, emphasizing the genetic and molecular determinants underlying their deregulation in SCCs.

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p63 at the Crossroads between Stemness and Metastasis in Breast Cancer

Cited by 50 publications

References 121 publications

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

TGFβ and EGF signaling orchestrates the AP-1- and p63 transcriptional regulation of breast cancer invasiveness

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

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