Cisplatin disrupts OCT1-DNMT1-piRNA epigenetic regulatory axis to suppress GAB2-mediated aggressiveness in OSCC

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Chemotherapy resistance in cancer is often linked to cellular plasticity.
• Non-coding RNAs (ncRNAs) play a role in chemotherapy-induced plasticity.
• piRNAs (PIWI-interacting RNAs) are emerging as key regulators in this process.

Purpose of the Study:

• To investigate the role of piRNAs in cisplatin resistance in oral squamous cell carcinoma (OSCC).
• To elucidate the molecular mechanisms by which cisplatin affects piRNA expression and function.
• To identify potential therapeutic targets for overcoming cisplatin resistance.

Main Methods:

• Analysis of piRNA expression in OSCC cells treated with cisplatin.
• Investigation of the epigenetic regulation of piRNA loci using techniques like DNA methylation analysis.
• Functional studies involving piRNA mimics or inhibitors to assess effects on cell proliferation, apoptosis, and DNA damage.
• Overexpression studies of target genes (e.g., GAB2) to validate findings.

Main Results:

• Cisplatin treatment significantly upregulates piRNA expression in OSCC cells, notably piR-hsa-30937.
• Cisplatin disrupts the OCT1-DNMT1 complex, leading to epigenetic derepression of piR-hsa-30937.
• piR-hsa-30937 sensitizes OSCC cells to cisplatin by targeting GAB2, suppressing proliferation, and enhancing apoptosis.
• GAB2 overexpression reverses these effects, conferring cisplatin resistance by activating NF-κB-mediated JNK suppression.

Conclusions:

• Cisplatin actively remodels the OCT1-DNMT1-piR-hsa-30937 axis in OSCC.
• Regulation of piRNA expression is a key mechanism mediating cisplatin cytotoxicity.
• Targeting the GAB2-mediated survival signaling pathway offers a potential strategy to enhance cisplatin efficacy in OSCC.