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Genomic analysis reveals HDAC1 regulates clinically relevant transcriptional programs in Pancreatic cancer
Carter A Wright1,2, Emily R Gordon2, Sara J Cooper3
1The University of Alabama in Huntsville, Huntsville, AL, 35899, USA.
Abstract:
Novel strategies are needed to combat multidrug resistance in pancreatic ductal adenocarcinoma (PDAC). We applied genomic approaches to understand mechanisms of resistance in order to better inform treatment and precision medicine. Altered function of chromatin remodeling complexes contribute to chemoresistance. Our study generates and analyzes genomic and biochemical data from PDAC cells overexpressing HDAC1, a histone deacetylase involved in several chromatin remodeling complexes. We characterized the impact of overexpression on drug response, gene expression, HDAC1 binding, and chromatin structure using RNA-sequencing and ChIP-sequencing for HDAC1 and H3K27 acetylation. Integrative genomic analysis shows that HDAC1 overexpression promotes activation of key resistance pathways including epithelial to mesenchymal transition, cell cycle, and apoptosis through global chromatin remodeling. Target genes are similarly altered in patient tissues and show correlation with patient survival. We also demonstrate that direct targets of HDAC1 that also show altered chromatin are enriched near genes associated with altered GTPase activity. HDAC1 target genes identified using in vitro methods and observed in patient tissues were used to develop a clinically relevant nine-transcript signature associated with patient prognosis. Integration of multiple genomic and biochemical data types enables understanding of multidrug resistance and tumorigenesis in PDAC, a disease in desperate need of novel treatment strategies.
Insights
Histone deacetylase 1 (HDAC1) overexpression drives multidrug resistance in pancreatic cancer by altering gene expression and chromatin. This study identifies a novel gene signature for predicting patient survival in pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Multidrug resistance (MDR) poses a significant challenge in treating pancreatic ductal adenocarcinoma (PDAC).
- Dysregulation of chromatin remodeling complexes, including histone deacetylases like HDAC1, is implicated in chemoresistance.
- Novel therapeutic strategies are urgently required to overcome resistance in PDAC.
Purpose of the Study:
- To investigate the role of HDAC1 overexpression in driving chemoresistance and tumorigenesis in PDAC.
- To elucidate the genomic and biochemical mechanisms underlying HDAC1-mediated drug resistance.
- To identify potential therapeutic targets and develop prognostic biomarkers for PDAC.
Main Methods:
- Genomic and biochemical analyses were performed on PDAC cells overexpressing HDAC1.
- RNA-sequencing and ChIP-sequencing (for HDAC1 and H3K27 acetylation) were utilized to assess gene expression and chromatin structure.
- Integrative genomic analysis was employed to connect in vitro findings with patient data.
Main Results:
- HDAC1 overexpression promotes activation of resistance pathways (epithelial-mesenchymal transition, cell cycle, apoptosis) via global chromatin remodeling.
- HDAC1 target genes and chromatin alterations in vitro mirror those found in patient tissues and correlate with survival.
- HDAC1 targets near genes with altered GTPase activity were identified, suggesting a link to tumorigenesis.
Conclusions:
- HDAC1 overexpression is a key driver of multidrug resistance and tumorigenesis in PDAC.
- A nine-transcript signature derived from HDAC1 target genes shows clinical relevance for PDAC prognosis.
- Integration of multi-omics data provides insights into PDAC resistance mechanisms, informing precision medicine approaches.
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