Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

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.

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

“…Hyperactive transcription of c-myc is driven by super-enhancer in human cancers [ 55 – 57 ]. A recent study demonstrated that TPL disrupts super-enhancers in pancreatic cancer cells [ 58 ]. The levels of c-myc protein were decreased to undetectable level after TPL treatment for 24 h. This powerful inhibitory effect is a comprehensive result from simultaneously repression protein stability and transcription of c-myc by TPL.…”

Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives

“…Triptolide has obvious inhibitory effects on pancreatic cancer. Triptolide, as a super-enhancer (SE) interacting agent, may exhibit its antitumor activity by interfering with cell cross-talk and signal transduction in pancreatic ductal adenocarcinoma 41 .…”

BRD4: An emerging prospective therapeutic target in glioma

“…BRD4 is widely expressed in human tissues, cancer cells, 13 , 21 cancer-associated fibroblasts, 22 and chronic inflammatory fibroblasts (e.g., liver, 23 lung, 24 cardiovascular, 25 and renal 26 ). In fact, BRD4 is considered the dominant transcriptional regulator within the BET protein family, 27 and it plays a significant role in the onset and progression of malignant human diseases, especially by controlling tumor cell proliferation and apoptosis, making it the most studied BET protein in cancer therapy.…”