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Pan-Cancer Analysis Reveals That E1A Binding Protein p300 Mutations Increase Genome Instability and Antitumor Immunity.

ABSTRACT: E1A binding protein p300 (EP300) is mutated in diverse cancers. Nevertheless, a systematic investigation into the associations of EP300 mutations with genome instability and antitumor immunity in pan-cancer remains lacking. Using the datasets from The Cancer Genome Atlas, we analyzed the correlations between EP300 mutations and genome instability and antitumor immune response in 11 cancer types. Compared to EP300-wild-type cancers, EP300-mutated cancers had significantly higher tumor mutation burden (TMB) in 10 cancer types. EP300-mutated cancers harbored a much higher fraction of microsatellite instable cancers in the colon and gastric cancers. EP300 was co-mutated with genes involved in DNA damage repair pathways in multiple cancers. Furthermore, compared to EP300-wild-type cancers, EP300-mutated cancers had significantly higher immune cytolytic activity scores and ratios of immune-stimulatory over immune-inhibitory signatures in diverse cancers. Also, EP300-mutated cancers showed significantly higher programmed death-ligand 1 (PD-L1) expression levels than EP300-wild-type cancers. The increased TMB, antitumor immune activity, and PD-L1 expression indicated a favorable response to immune checkpoint inhibitors (ICIs) in EP300-mutated cancers, as evident in three cancer cohorts treated with ICIs. Thus, the EP300 mutation could be a predictive biomarker for the response to immunotherapy.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8488206 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTumour-associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.MethodsThis study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1-derived TAM model. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1-derived TAMs was performed with lentivirus, and the impact of THP1-derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA-chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA-protein interaction was studied by RNA immunoprecipitation and RNA pull-down.ResultsOur data showed that the transcription factor CTCF (CCCTC-binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper-accessible chromatin regions when compared to monocytes. High infiltration of CTCF+ TAMs was significantly associated with poor prognosis in PDAC patients. Knockdown of CTCF in THP1-derived TAMs led to the down-regulation of specific markers for M2-polarised TAMs, including CD206 and CD163. When THP1-derived TAMs with CTCF knockdown, they showed a decreased ability of invasion and metastasis. Further integrative analysis of multi-omics data revealed that prostaglandin-endoperoxide synthase 2 (PTGS2) and PTGS2 antisense NF-κB1 complex-mediated expression regulator RNA (PACERR) were critical downstream targets of CTCF and positively correlated with each other, which are closely situated on a chromosome. Knockdown of PACERR exhibited a similar phenotype as observed in CTCF knockdown THP1-derived TAMs. Moreover, PACERR could directly bind to CTCF and recruit histone acetyltransferase E1A binding protein p300 to the promoter regions of PACERR and PTGS2, thereby enhancing histone acetylation and gene transcription, promoting the M2 polarization of TAMs in PDAC.ConclusionsOur study demonstrated a novel epigenetic regulation mechanism of promoting pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.

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Pan-Cancer Analysis Reveals That E1A Binding Protein p300 Mutations Increase Genome Instability and Antitumor Immunity.

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