A non-canonical Hippo pathway represses the expression of deltaNp63
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228680 | GEO | 2024/02/07
REPOSITORIES: GEO
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Project description:Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here we reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC.
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Project description:Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here we reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC. Gene expression profiling of untransformed keratinocytes (HaCaT) with and without ablated endogenous p63 via lentiviral shRNA.
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Project description:Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here we reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC. Gene expression profiling of HNSCC cells with and without ablated endogenous p63 via lentiviral shRNA
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Project description:A non-canonical Hippo pathway represses the expression of deltaNp63
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Project description:Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here we reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC. Gene expression profiling of HNSCC cells with and without ablated endogenous ACTL6A via lentiviral shRNA.
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Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of head-and-neck, skin, breast, urothelium, etc. to maintain the well-differentiated phenotype. TP63 has two transcription start sites at exon 1 and exon 3’ to produce TAp63 and DeltaNp63 isoforms, respectively. The major protein, DeltaNp63alpha, epigenetically activates genes essential for epidermal/craniofacial differentiation, including DeltaNp63 itself. To examine whether weakly expressed TAp63 has a specific role, we disrupted exon 1 by CRISPR-Cas9 homology directed repair in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells, either by monoallelic GFP cassette insertion paired with a frameshift deletion allele or by biallelic GFP cassette insertion, caused DeltaNp63 silencing. Loss of keratinocyte-specific gene expression, switching of intermediate filaments from KRT(s) to VIM, and suppression of cell-cell and cell-matrix adhesion components indicated core events of epithelial mesenchymal transition. Most of the positively and negatively impacted genes including DeltaNp63 displayed local DNA methylation changes. Furthermore, DeltaNp63 expression was partially rescued by transfection of TAp63alpha followed by incubation with DNA methyltransferase inhibitor Zebularine. TAp63, as a minor part of TP63 gene, may possibly be involved in the auto-activation mechanism of DeltaNp63 by which keratinocyte-specific epigenome is maintained in SCC.
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