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DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications
1Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia. kahkeng@usm.my.
Background:
Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating cancer types with a 5-year survival rate of only 9%. PDAC is one of the leading causes of cancer-related deaths in both genders. Epigenetic alterations may lead to the suppression of tumor suppressor genes, and DNA methylation is a predominant epigenetic modification. DNA methyltransferase 1 (DNMT1) is required for maintaining patterns of DNA methylation during cellular replication. Accumulating evidence has implicated the oncogenic roles of DNMT1 in various malignancies including PDACs.
Conclusions:
Herein, the expression profiles, oncogenic roles, regulators and inhibitors of DNMT1 in PDACs are presented and discussed. DNMT1 is overexpressed in PDAC cases compared with non-cancerous pancreatic ducts, and its expression gradually increases from pre-neoplastic lesions to PDACs. DNMT1 plays oncogenic roles in suppressing PDAC cell differentiation and in promoting their proliferation, migration and invasion, as well as in induction of the self-renewal capacity of PDAC cancer stem cells. These effects are achieved via promoter hypermethylation of tumor suppressor genes, including cyclin-dependent kinase inhibitors (e.g., p14, p15, p16, p21 and p27), suppressors of epithelial-mesenchymal transition (e.g., E-cadherin) and tumor suppressor miRNAs (e.g., miR-148a, miR-152 and miR-17-92 cluster). Pre-clinical investigations have shown the potency of novel non-nucleoside DNMT1 inhibitors against PDAC cells. Finally, phase I/II clinical trials of DNMT1 inhibitors (azacitidine, decitabine and guadecitabine) in PDAC patients are currently underway, where these inhibitors have the potential to sensitize PDACs to chemotherapy and immune checkpoint blockade therapy.
Insights
DNA methyltransferase 1 (DNMT1) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cancer progression. Novel DNMT1 inhibitors show promise in clinical trials for treating PDAC, potentially enhancing chemotherapy and immunotherapy effectiveness.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 9%.
- Epigenetic alterations, particularly DNA methylation, are crucial in cancer development.
- DNA methyltransferase 1 (DNMT1) plays a key role in maintaining DNA methylation patterns and has oncogenic roles in various cancers, including PDAC.
Purpose of the Study:
- To review the expression, functions, regulators, and inhibitors of DNMT1 in PDAC.
- To highlight the oncogenic roles of DNMT1 in PDAC progression.
- To discuss the therapeutic potential of DNMT1 inhibitors in PDAC treatment.
Main Methods:
- Review of existing literature on DNMT1 in PDAC.
- Analysis of DNMT1 expression profiles in PDAC tissues.
- Evaluation of preclinical data on DNMT1 inhibitors.
- Summary of ongoing clinical trials involving DNMT1 inhibitors for PDAC.
Main Results:
- DNMT1 is overexpressed in PDAC compared to normal pancreatic ducts, with increasing levels from pre-neoplastic lesions to PDAC.
- DNMT1 promotes PDAC progression by suppressing tumor suppressor genes (e.g., CDKN2A, CDH1) and miRNAs via promoter hypermethylation.
- DNMT1 contributes to PDAC cell differentiation suppression, proliferation, migration, invasion, and cancer stem cell self-renewal.
Conclusions:
- DNMT1 is a significant oncogenic driver in PDAC, contributing to its aggressive phenotype.
- Novel non-nucleoside DNMT1 inhibitors demonstrate efficacy against PDAC cells in preclinical studies.
- DNMT1 inhibitors (azacitidine, decitabine, guadecitabine) are in Phase I/II clinical trials for PDAC, with potential to sensitize tumors to chemotherapy and immunotherapy.
