Abstract
We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.
Highlights
Polycomb group proteins (PcGs) can remodel chromatin by influencing the degree of compaction, leading to epigenetic gene silencing
No significant changes were observed in the proliferation and cellular viability of normal human pancreatic ductal epithelial (HPDE) cells which are highly gemcitabine-sensitive, as well as two other normal cell lines (293T and MCF-10A) (Figs. 1A-B, S1)
These results demonstrate that deazaneplanocin A (DZNep) selectively imparts cytotoxic effects to pancreatic cancer cells without significant impairment of proliferation in normal pancreatic epithelial cells
Summary
Polycomb group proteins (PcGs) can remodel chromatin by influencing the degree of compaction, leading to epigenetic gene silencing. Polycomb Repressive Complex 2 (PRC2), one of the two classes of PcGs, induces histone methyltransferase activity primarily by trimethylating histone H3 at lysine 27 (H3K27me3), mediating silencing of tumor suppressor genes. As a marker of advanced and metastatic disease in many solid tumors, EZH2 overexpression has been reported in pancreatic cancers, those that are poorly differentiated [6,7]. EZH2 depletion led to cell cycle arrest at the G1/S transition, suggesting the protein may repress the tumor suppressing p27 gene [10]. Positive correlations have been observed between EZH2 expression and advanced pancreatic cancer stage and grade in patients [11]. In gemcitabine-treated patients, significantly longer survival was observed in patients with low rather than high EZH2 expression [12]. EZH2 may be a significant prognostic value for overall survival in pancreatic cancer patients [13]
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