Reprogramming Tumor Biology: Targeting Epigenetic Pathways in Pancreatic Cancer

Pancreatic cancer (PC) currently ranks as the third leading cause of cancer-related mortality worldwide, with projections indicating it may rise to the second position by ۲۰۴۰ (۱). A significant contributor to the poor prognosis associated with advanced-stage PC is the lack of effective therapeutic strategies, which primarily focus on management. Recent studies have identified epigenetic modifications, including alterations in histone tail modifications and DNA methylation patterns, as key factors in the rapid progression of this disease. These modifications enable cells to adjust gene expression levels without altering the underlying DNA sequence (۲). The reversible nature of these epigenetic changes presents a promising opportunity to restore the epigenetic landscape to its pre-disease state. Targeting DNA Methylation Current research on DNA methylation primarily investigates the efficacy of DNA methyltransferase (DNMT) inhibitors as potential cancer therapies. Recent findings indicate that PC stem cells exhibit elevated levels of DNMT۱, increased DNA methylation, and a loss of stemness when DNMT۱ is inhibited pharmacologically or genetically (۳). Moreover, high expression levels of DNMT۳a in PC correlate strongly with poor patient prognosis. Knockdown of DNMT۳a leads to reduced cyclin D۱ expression, which induces apoptosis and cell cycle arrest (۴). Notably, DNMT inhibitors (DNMTis) such as guadecitabine, decitabine, and ۵-aza are currently being evaluated in Phase I/II clinical trials for their potential to enhance the sensitivity of pancreatic ductal adenocarcinoma cells to immune checkpoint blockade therapy and chemotherapy (۵). Given these recent advancements, DNMTis have shown promisingly for future cancer therapies, particularly in efforts to reprogram tumors. Targeting Histone Modifications Histone acetylation and deacetylation are regulated by two key enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs), which play crucial roles in gene regulation (۶). One notable marker associated with PC is aberrant H۳K۹me۳, typically indicating gene silencing. G۹a, a histone methyltransferase responsible for this modification, has emerged as a prominent target for inhibition in PC treatment. Additionally, in various cancer types characterized by G۹a overexpression, G۹a inhibitors have been shown to decrease proliferation and induce apoptosis (۷). Furthermore, EZH۲, a functional component of the polycomb repressive complex ۲ (PRC۲), methylates H۳K۲۷ across multiple cancers, contributing to the epigenetic repression of tumor suppressor genes (۸). Combination therapy using G۹a and EZH۲ inhibitors has demonstrated efficacy in reducing H۳K۹ and H۳K۲۷ methylation in breast cancer, by inhibiting colony formation and cell proliferation (۹). Besides, HDACis, as SAHA and CUDC-۱۰۱, represent another epigenetic strategy for treating PC, which could downregulate anti-apoptotic proteins such as XIAP and survivin in PC cells (۱۰). In summary, the inhibition of histone-modifying enzymes, along with the application of HDACis, presents a multifaceted approach to reversing epigenetic alterations in PC, thus enhancing therapeutic efficacy and offering new avenues for treatment. Conclusion The variability in mutations and responses observed across different tumor samples underscores the necessity for personalized medicine to enhance therapeutic efficacy and tailor epigenetic-based treatments for individual patients. Numerous epigenetic regulators can be effectively targeted using small molecule inhibitors; therefore, further investigation into these mechanisms is warranted to optimize treatment strategies for pancreatic cancer.

کلیدواژه ها:

Pancreatic cancer ، Epigenetics ، Tumor reprogramming ، DNA methylation ، Histone modification