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Loss of WWOX Drives Cutaneous Squamous Cell Carcinoma (cSCC) through Regulating EMT [RNA-Seq]

ABSTRACT: Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common skin cancer, with a rising incidence in recent years. Through protein-protein interactions, the WW domain-containing oxidoreductase (WWOX) has been found to be a key player in many cellular processes, including DNA repair, apoptosis, metabolism, and transcriptional regulation. WWOX loss has been reported in many malignancies, including cSCC, suggesting a tumor suppressor role, but its function as a skin cancer antagonist and the underlying molecular mechanisms are not yet fully understood. To better understand WWOX's role in cSCC, we generated K14-Cre;Wwox;Trp53 conditional knock-out mice, leading to the development of cSCC. Strikingly, mice with ablated WWOX developed cSCC with increased penetrance and earlier onset. Characterization of cSCC morphology, immune markers, and transcriptional signatures revealed poorly differentiated cSCC with epithelial-to-mesenchymal transition (EMT) traits in tumors lacking WWOX compared to their controls. The hyperplastic phenotype of the epidermis in conditionally Wwox-knock-out mice was observed at an early age and impacted the surrounding microenvironment as well. Based on WWOX's known interaction with and stabilization of the transcription factor p63, we proposed that epidermal WWOX loss reduces p63 levels, destabilizing the tissue's epithelial integrity. Indeed, our findings confirmed this mechanism, demonstrating that diminished p63 impairs the epidermal protective barrier and accelerates the progression of aggressive cSCC. The WWOX-p63 correlation was also observed in human cSCC samples, inversely related to tumor stage. These findings were further supported in keratinocytes and cSCC human cell line models, where WWOX deficiency led to reduced p63 expression, concomitant with enhanced tumorigenic potential and migratory capacity.

ORGANISM(S): Mus musculus

PROVIDER: GSE300269 | GEO | 2026/04/13

REPOSITORIES: GEO

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Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFβ responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFβ signaling in advanced breast cancer.

Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFM-NM-2 responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFM-NM-2 signaling in advanced breast cancer. We compared two independent shRNAs: shWWOX-A and shWWOX-B with 3 biological replicates each one, targeting different regions of the WWOX transcript as a means of ruling out any potential off-target effects.

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Loss of WWOX Drives Cutaneous Squamous Cell Carcinoma (cSCC) through Regulating EMT [RNA-Seq]

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