Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state

• Published in: Cell death & disease Vol. 15; no. 1; pp. 89 - 14
• Main Authors: He, Bo, Stoffel, Lauren, He, Clifford Jiajun, Cho, Kumsun, Li, Albert M., Jiang, Haowen, Flowers, Brittany M., Nguyen, Kha The, Wang, Kelly Wen, Zhao, Audrey Yixin, Zhou, Meng-Ning, Ferreira, Sofia, Attardi, Laura D., Ye, Jiangbin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-01-2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/106; 14; 14/34; 38; 38/39; 38/91; 45; 631/67/2329; 692/699/67/1504/1713; Acetylation; Adenocarcinoma; Animals; Antibodies; Antitumor agents; Apoptosis; Azacitidine - pharmacology; Biochemistry; Biomedical and Life Sciences; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell viability; DNA methylation; Epigenesis, Genetic; Epigenetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene regulation; Genetic engineering; Genotype & phenotype; Immunology; Life Sciences; Mice; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Phenotypes; Transcriptomics; Tumors; Vitamin D; Vitamin D - pharmacology; Vitamin D receptors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06460-9

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2′-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.