STAT3 and p63 in the Regulation of Cancer Stemness

Wei, Shixiong; Li, Jialin; Tang, Mingbo; Zhang, Kewei; Gao, Xinliang; Fang, Linan; Liu, Wei

doi:10.3389/fgene.2022.909251

Cited by 9 publications

(7 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In favour of an indirect mechanism, we posit that HIF1α perturbation, which inhibits mesenchymal gene expression, destabilises p63 and hence the E/M state. Moreover, GPx2 KD may regulate this process via oxidation/inactivation of tyrosine phosphatases by ROS [ 47 ], which results in EGFR/STAT3 signalling, leading to p63 gene transcription [ 48 , 49 ]. Otherwise, HIF1α may activate Wnt signalling in hypoxic niches, thereby upregulating p63, a well-documented Wnt target gene [ 47 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α

Ren,

Dharmaratne,

Liang

et al. 2024

Br J Cancer

View full text Add to dashboard Cite

Background Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, the tumour cell subpopulations and transcriptional regulators governing these processes remained unknown. Methods We used single-cell transcriptomics to decipher the tumour cell subpopulations stimulated by GPx2 KD in the PyMT mammary tumour and paired pulmonary metastases. We analyzed the EMT spectrum across the various tumour cell clusters using pseudotime trajectory analysis and elucidated the transcriptional and metabolic regulation of the hybrid EMT state. Results Integration of single-cell transcriptomics between the PyMT/GPx2 KD primary tumour and paired lung metastases unraveled a basal/mesenchymal-like cluster and several luminal-like clusters spanning an EMT spectrum. Interestingly, the luminal clusters at the primary tumour gained mesenchymal gene expression, resulting in epithelial/mesenchymal subpopulations fueled by oxidative phosphorylation (OXPHOS) and glycolysis. By contrast, at distant metastasis, the basal/mesenchymal-like cluster gained luminal and mesenchymal gene expression, resulting in a hybrid subpopulation using OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated in all hybrid clusters, implying a role in regulating partial EMT and MET at primary and distant sites, respectively. Importantly, these effects were reversed by HIF1α loss or GPx2 gain of function, resulting in metastasis suppression. Conclusions Collectively, these results underscored a dramatic effect of redox signaling on p63 activation by HIF1α, underlying phenotypic and metabolic plasticity leading to mammary tumour metastasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α

Ren,

Dharmaratne,

Liang

et al. 2024

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Numerous studies have reported that aberrant activation of STAT3 signaling promotes tumor growth, 46 invasion, metastasis, 48 and resistance to therapy. 49 The JAK/STAT and Wnt-β-catenin pathways have been identified as pivotal players in tumorigenesis. Notably, research has demonstrated a direct interaction between STAT3 and β-catenin in the nucleus, 50 with STAT3 positively regulating β-catenin’s transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

Huang,

Xiao,

Lan

et al. 2024

Int J Oral Sci

View full text Add to dashboard Cite

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor progression. These findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

show abstract

“…In addition, EZH2-activated RUNX3 acts as an inhibitor of both SETD1 and ΔNp63α [ 194 ]. ΔNp63 is often overexpressed in SCCs, in which it acts as a master regulator of CSCs maintenance via its functional connection with signal transducer and activator of transcription 3 (STAT3), assigning STAT3 induces ΔNp63 expression through binding to its promoter [ 195 – 197 ]. The gene encoding the chromatin-modifying protein that ACTL6A (Actin-like protein 6 A) is coamplified with p63 locus in HNSCC and induces a CSC phenotype characterized by undifferentiated regenerative proliferation.…”

Section: P63 and Cancer Stem Cell In Epithelial Tumormentioning

confidence: 99%

p63: a crucial player in epithelial stemness regulation

Li,

Giovannini,

Wang

et al. 2023

Oncogene

View full text Add to dashboard Cite

Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, is an indispensable factor for their biological activities during epithelial development. The diversity of p63 isoforms expressed in distinct tissues allows this transcription factor to have a wide array of effects. p63 coordinates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. Through the regulation of these biological processes, p63 contributes to, not only normal epithelial development, but also epithelium-derived cancer pathogenesis. In this review, we provide an overview of the role of p63 in epithelial stemness regulation, including self-renewal, differentiation, proliferation, and senescence. We describe the differential expression of TAp63 and ΔNp63 isoforms and their distinct functional activities in normal epithelial tissues and in epithelium-derived tumors. Furthermore, we summarize the signaling cascades modulating the TAp63 and ΔNp63 isoforms as well as their downstream pathways in stemness regulation.

show abstract

STAT3 and p63 in the Regulation of Cancer Stemness

Cited by 9 publications

References 33 publications

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

p63: a crucial player in epithelial stemness regulation

Contact Info

Product

Resources

About