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Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155187 | GEO | 2021/03/05

REPOSITORIES: GEO

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Bromodomain protein BRDT directs ΔNp63 function and super-enhancer activity in a subset of esophageal squamous cell carcinomas.

Project description:Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer with a particularly high prevalence in certain geographical regions and a poor prognosis with a 5-year survival rate of 15-25%. Despite numerous studies characterizing the genetic and transcriptomic landscape of ESCC, there are currently no effective targeted therapies. In this study, we used an unbiased screening approach to uncover novel molecular precision oncology targets for ESCC and identified the bromodomain and extraterminal (BET) family member bromodomain testis-specific protein (BRDT) to be uniquely expressed in a subgroup of ESCC. Experimental studies revealed that BRDT expression promotes migration but is dispensable for cell proliferation. Further mechanistic insight was gained through transcriptome analyses, which revealed that BRDT controls the expression of a subset of ΔNp63 target genes. Epigenome and genome-wide occupancy studies, combined with genome-wide chromatin interaction studies, revealed that BRDT colocalizes and interacts with ΔNp63 to drive a unique transcriptional program and modulate cell phenotype. Our data demonstrate that these genomic regions are enriched for super-enhancers that loop to critical ΔNp63 target genes related to the squamous phenotype such as KRT14, FAT2, and PTHLH. Interestingly, BET proteolysis-targeting chimera, MZ1, reversed the activation of these genes. Importantly, we observed a preferential degradation of BRDT by MZ1 compared with BRD2, BRD3, and BRD4. Taken together, these findings reveal a previously unknown function of BRDT in ESCC and provide a proof-of-concept that BRDT may represent a novel therapeutic target in cancer.

| S-EPMC8257622 | biostudies-literature

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

Project description:Using an unbiased method, we found a testis-specific epigenetic reader protein BRDT to be expressed and functional active in a significant portion of ESCC patients. Mechanistically, BRDT co-localizes with ΔNp63, a defining transcription factor for squamous subtype, at selected super-enhancers to regulate ΔNp63-dependent transcription programs to promote cell migration. Pharmacologically depleting BRDT resembles the effects of knock-down of BRDT, thus providing a promising clinical approach for precision medicine in a subset of ESCC.

2021-03-05 | GSE155184 | GEO

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

2021-03-05 | GSE155186 | GEO

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

2021-03-05 | GSE155183 | GEO

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas

| PRJNA648936 | ENA

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

| PRJNA648935 | ENA

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

| PRJNA648938 | ENA

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

| PRJNA648933 | ENA

Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein.

Project description:The association between histone acetylation and replacement observed during spermatogenesis prompted us to consider the testis as a source for potential factors capable of remodelling acetylated chromatin. A systematic search of data banks for open reading frames encoding testis-specific bromodomain-containing proteins focused our attention on BRDT, a testis-specific protein of unknown function containing two bromodomains. BRDT specifically binds hyperacetylated histone H4 tail depending on the integrity of both bromodomains. Moreover, in somatic cells, the ectopic expression of BRDT triggered a dramatic reorganization of the chromatin only after induction of histone hyperacetylation by trichostatin A (TSA). We then defined critical domains of BRDT involved in its activity. Both bromodomains of BRDT, as well as flanking regions, were found indispensable for its histone acetylation-dependent remodelling activity. Interestingly, we also observed that recombinant BRDT was capable of inducing reorganization of the chromatin of isolated nuclei in vitro only when the nuclei were from TSA-treated cells. This assay also allowed us to show that the action of BRDT was ATP independent, suggesting a structural role for the protein in the remodelling of acetylated chromatin. This is the first demonstration of a large-scale reorganization of acetylated chromatin induced by a specific factor.

| S-EPMC165724 | biostudies-literature

The Role of Bromodomain Testis-Specific Factor, BRDT, in Cancer: A Biomarker and A Possible Therapeutic Target.

Project description:Cancer cells have recently been shown to activate hundreds of normally silent tissue-restricted genes, including a specific subset associated with cancer progression and poor prognosis. Within these genes, a class of testis-specific genes designed as cancer/testis, attracted special attention because of their oncogenic roles as well as their potential use in immunotherapy. Here we focus on one of these genes encoding the testis-specific member of the bromodomain and extra-terminal (BET) family, known as BRDT. Aberrant activation of BRDT was first detected in lung cancers. In this study, we report that the frequency of BRDT's aberrant activation in lung cancer varies according to the histological subtypes and in contrast with other cancer/testis genes, it is rarely expressed in other solid tumours. The functional characterization of BRDT in its physiological setting in male germ cells is now painting a clear portrait of its normal activity and also suggests possible underlying oncogenic activities, when the gene is ectopically activated in cancers. Also, these functional studies of BRDT point to specific anti-cancer therapeutic strategies that could be used to "high-jack" BRDT's action and turn it against cancer cells, which express this gene. Finally, BRDT's expression could be used as a biomarker for cell sensitivity to BET bromodomain inhibitors, which have become newly available as anti-cancer drugs.

| S-EPMC5448322 | biostudies-literature

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