P63 and its co-binding factor Znf148 cooperate to control squamous cell carcinoma proliferation
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ABSTRACT:
PROVIDER: PRJNA1000600 | ENA |
REPOSITORIES: ENA
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Project description:Head and neck squamous cell carcinoma (HNSCC) are common and aggressive malignancies, and little progress has been made in improving outcomes for patients. HNSCC exhibit frequent overexpression of the p53-related transcription factor TP63. Here, we show that ZNF148 is an important partner in p63-driven tumorigenesis. Mechanistically, while ZNF148 alone binds CCND1 gene promoter, the p63-ZNF148 complex co-binds a CCND1 upstream enhancer leading to an enhancer-derived RNAs (eRNA3) acting as cis-regulatory elements for CCND1 transcription. The eRNA3 p63/ZNF148-dependent transcription is required to support high-rate proliferation in HNSCC. Interestingly, p63/ZNF148, eRNA3 and cyclin D1 expression is highly co-correlated in primary HNSCC, including laryngeal squamous cell carcinoma (LSCC). Their co-expression correlated to tumor stage and lymph nodes positivity. These results revealed a strong cooperation of the two transcription factors, p63 and ZNF148, as HNSCC oncogenic drivers. Altogether, these findings provide a framework to facilitate categorization of HNSCC sub-types, prognostic/diagnostic biomarkers, and a foundation for development of new therapies.
2025-07-02 | GSE239709 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a common and aggressive malignancy. While significant advances have been made in the management of low-grade cancer, treatment of advanced HNSCC remains challenging. Here, we used a proteomic approach to discover novel binding partners of the oncogene p63, the most frequently amplified transcription factor in HNSCC. We identified a zinc finger protein, ZNF148, which is coexpressed and physically binds p63 in carcinoma cells. Genome occupancy analyses identified a functional transcribed enhancer-derived RNA (eRNA) upstream of the CCND1 gene occupied by both factors. Mechanistically, p63 and ZNF148 control transcription of this eRNA, leading to overexpression of cyclin D1 to reinforce tumour cell proliferation. Importantly, this axis is specific for cancer cells and remains inactive in normal epithelial cells. The expression levels of these factors and the eRNA are positively correlated in cancer and associated with advanced stage and metastasis. Collectively, our data reveal a novel molecular pathway controlling HNSCC progression and identifies potential selective targets for cancer treatment.
2025-06-18 | GSE279161 | GEO
Project description:Aberrant expression of transcriptional regulators can affect oncogenic gene expression programs in cancer. Mutations in the tumor suppressor p53 are commonly found in UV-damaged skin and protect damaged epidermal cells from senescence and or oncogene-induced apoptosis, favoring cancer formation. In contrast, the other p53 family members p63 and p73 are rarely mutated in cancer and p63 is often amplified or overexpressed in lung, esophagus, and head and neck squamous cell carcinoma (SCC). Here, we demonstrate that both p63 and p73 are required for cell proliferation in epidermal cells and in skin SCC and are overexpressed in preneoplastic lesions and in skin SCCs. p63/p73 form heterotetramers and co-occupy thousands of regulatory regions, jointly controlling a transcriptional program that promotes cell proliferation and tumorigenesis. The combination of gene knockdown with transcriptomic and epigenetic analyses revealed that p63 and p73 control a transcriptional feed-forward circuit that sustains cell proliferation. We find that in skin SCC a key signaling pathway downstream of p63/p73 is the Epidermal Growth Factor Receptor (EGFR)/MAP kinase. p63/p73 directly and positively control transcription of the EGFR ligands, among which amphiregulin (AREG) is the most highly expressed in skin SCC. Like p63/p73, AREG is critical to maintain skin SCC proliferative potential, anchorage independent growth, and to promote tumorigenesis. Thus, p63 and p73 act as oncogenic drivers in skin SCC, with AREG being a crucial non-cell-autonomous effector downstream of p63 and p73 in skin SCC formation.
2026-08-28 | GSE235461 | GEO
Project description:Aberrant expression of transcriptional regulators can affect oncogenic gene expression programs in cancer. Mutations in the tumor suppressor p53 are commonly found in UV-damaged skin and protect damaged epidermal cells from senescence and or oncogene-induced apoptosis, favoring cancer formation. In contrast, the other p53 family members p63 and p73 are rarely mutated in cancer and p63 is often amplified or overexpressed in lung, esophagus, and head and neck squamous cell carcinoma (SCC). Here, we demonstrate that both p63 and p73 are required for cell proliferation in epidermal cells and in skin SCC and are overexpressed in preneoplastic lesions and in skin SCCs. p63/p73 form heterotetramers and co-occupy thousands of regulatory regions, jointly controlling a transcriptional program that promotes cell proliferation and tumorigenesis. The combination of gene knockdown with transcriptomic and epigenetic analyses revealed that p63 and p73 control a transcriptional feed-forward circuit that sustains cell proliferation. We find that in skin SCC a key signaling pathway downstream of p63/p73 is the Epidermal Growth Factor Receptor (EGFR)/MAP kinase. p63/p73 directly and positively control transcription of the EGFR ligands, among which amphiregulin (AREG) is the most highly expressed in skin SCC. Like p63/p73, AREG is critical to maintain skin SCC proliferative potential, anchorage independent growth, and to promote tumorigenesis. Thus, p63 and p73 act as oncogenic drivers in skin SCC, with AREG being a crucial non-cell-autonomous effector downstream of p63 and p73 in skin SCC formation.
2026-08-28 | GSE235459 | GEO
Project description:This study was designed to examine the requirement for the p63 transcription factor in Squamous Cell Carcinoma (SCC) tumor maintenance in an in vivo murine system. A tamoxifen-inducible Keratin 14-driven Cre recombinase transgene was used to conditionally excise p63 in advanced murine SCC tumors. These data show the context-dependent regulation of p63 target genes in cancer. Total RNA from murine Squamous Cell Carcinoma tumors was examined 1-3 days following genomic excision of TP63 in Keratin 14-expressing tumor cells.
2013-08-06 | E-GEOD-45929 | biostudies-arrayexpress
Project description:p63 and p73 cooperate to promote cutaneous squamous cell carcinoma through largely overlapping transcriptional programs
| PRJNA986102 | ENA
Project description:This study was designed to examine the requirement for the p63 transcription factor in Squamous Cell Carcinoma (SCC) tumor maintenance in an in vivo murine system. A tamoxifen-inducible Keratin 14-driven Cre recombinase transgene was used to conditionally excise p63 in advanced murine SCC tumors. These data show the context-dependent regulation of p63 target genes in cancer.
2013-08-06 | GSE45929 | GEO
Project description:A central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct, p53-independent roles in development and cancer: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. Here, we identify a new and physiologically important mechanism of p63/p73 cross-talk which governs the balance between pro-survival and pro-apoptotic programs in both human and murine squamous cell carcinoma. Through comprehensive profiling of p63-regulated microRNAs (miRs), we identified a subset which target p73 for inhibition, including miR-193a-5p, a direct endogenous transcriptional target repressed by p63 and activated by pro-apoptotic p73 isoforms in both normal cells and tumor cells in vivo. Consequently, chemotherapy treatment causes p63/p73-dependent induction of this miR, thereby limiting chemosensitivity due to miR-mediated feedback control of p73. We demonstrate that interrupting this feedback by inhibiting miR-193a suppresses tumor cell viability and induces dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, miR-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition provides a new therapeutic opportunity in p53-deficient tumors. Knockdown of endogenous p63 by p63-directed or control lentiviral shRNA in JHU-029 human SCC cells at 48h, in duplicate experiments. Array analysis showing the fold-change and direction of change for all miRs regulated > 1.5-fold in p63-ablated versus control samples
2010-11-23 | E-GEOD-25524 | biostudies-arrayexpress
Project description:SOX2 is a transcription factor essential for pluripotent stem cells, and development and maintenance of squamous epithelium. We previously reported SOX2 an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here we demonstrate in SCCs that SOX2 interacts with another master squamous transcription factor p63, and through ChIP-seq show that genomic occupancy of SOX2 overlaps with that of p63 at a large number of loci and that they cooperatively regulate gene expression including ETV4, which we find essential for SOX2-amplified SCC cell survival. Furthermore, SOX2 binds to distinct genomic loci in SCCs than in embryonic stem cells and the SOX2-p63 coordinate binding is unique to SCC. In addition, a subset of SOX2 genomic binding sites in SCC that lack p63 co-occupancy are co-occupied by the AP-1 transcriptional complex. These demonstrate that SOX2’s actions in SCC differ substantially from its role in pluripotency and identify novel SOX2 interactions that will enable deeper characterization of SOX2’s function in SCC. SOX2 and p63 ChIP-seq from three lung and esophageal squamous carcinoma cell lines with amplification of SOX2 as well as SOX2 ChIP-seq from an ES cells.
2014-03-12 | E-GEOD-46837 | biostudies-arrayexpress
Project description:A central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct, p53-independent roles in development and cancer: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. Here, we identify a new and physiologically important mechanism of p63/p73 cross-talk which governs the balance between pro-survival and pro-apoptotic programs in both human and murine squamous cell carcinoma. Through comprehensive profiling of p63-regulated microRNAs (miRs), we identified a subset which target p73 for inhibition, including miR-193a-5p, a direct endogenous transcriptional target repressed by p63 and activated by pro-apoptotic p73 isoforms in both normal cells and tumor cells in vivo. Consequently, chemotherapy treatment causes p63/p73-dependent induction of this miR, thereby limiting chemosensitivity due to miR-mediated feedback control of p73. We demonstrate that interrupting this feedback by inhibiting miR-193a suppresses tumor cell viability and induces dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, miR-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition provides a new therapeutic opportunity in p53-deficient tumors.
2010-11-23 | GSE25524 | GEO