Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Human intestinal peptide transporter PEPT1 is frequently repressed in colorectal cancer (CRC).
• The link between PEPT1 expression and sensitivity to ubenimex, a common CRC treatment, remains unclear.
• Understanding PEPT1 regulation is crucial for improving CRC therapy.

Purpose of the Study:

• To confirm PEPT1 suppression in CRC and investigate the epigenetic mechanisms driving this repression.
• To explore the role of epigenetic PEPT1 activation in enhancing CRC response to ubenimex.
• To evaluate the efficacy of combined decitabine and ubenimex therapy in CRC models.

Main Methods:

• Real-time quantitative polymerase chain reaction and western blotting to assess PEPT1 levels.
• Bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays to study epigenetic regulation.
• In vitro and xenograft models to evaluate combination therapy effects.

Main Results:

• PEPT1 suppression was confirmed in CRC.
• DNMT1-mediated DNA methylation and HDAC1-mediated histone deacetylation were identified as key mechanisms for PEPT1 repression.
• Epigenetic activation of PEPT1, through sequential decitabine and ubenimex therapy, improved CRC response.
• Increased DNMT1 and HDAC1 expression correlated with poor ubenimex response.

Conclusions:

• Epigenetic silencing of PEPT1, driven by elevated DNMT1 and HDAC1, significantly impairs CRC sensitivity to ubenimex.
• Targeting these epigenetic pathways offers a potential strategy to overcome ubenimex resistance in CRC.
• Combination therapy with epigenetic modifiers and ubenimex shows promise for CRC treatment.