Abstract
The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.
Highlights
Pancreatic cancer (PC), currently the third leading cause of cancer-related death in the United States[1], is projected to be the second leading cause of cancer-related death before 20302
Many of the ChIP signals overlapped between the H3K27 acetylation (H3K27ac) and BRD4 marks, which supports the notion that these elements are active SEs in the cell lines
SE-associated genes in cancer-associated fibroblasts (CAFs) were mostly associated with processes such as desmoplasia, fibrosis, or those related to the extracellular matrix (e.g., COL1A1, COL1A2, TGFBI), which is abundant in advanced-stage Pancreatic ductal adenocarcinoma (PDAC) (Fig. 1c, d)
Summary
Pancreatic cancer (PC), currently the third leading cause of cancer-related death in the United States[1], is projected to be the second leading cause of cancer-related death before 20302. Noel et al Oncogenesis (2020)9:100 expression implicate the role of super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and diseased cells[8,9]. SEs are transcriptional regulatory elements composed of regular enhancers clustered together in close genomic proximity and bear active chromatin marks such as H3K27 acetylation (H3K27ac) and BRD4 occupancy. Since the first reports of SEs in human embryonic stem cells, there is mounting evidence for their role in regulating cell identity and state in numerous diseases including cancer, where they promote oncogenic transcriptional dependencies[10,11]. Inhibitors of CDK7, a subunit of the transcription factor complex TFIIH, were shown to disrupt SE networks in cancer cells and exert potent antitumor activity[12,13,14]. The effects of other TFIIH-targeted molecules have not been reported
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