The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase with largely uncharacterized functions.
• Cancer cells often develop resistance to chemotherapy drugs like cisplatin, necessitating research into underlying resistance mechanisms.

Purpose of the Study:

• To elucidate the molecular mechanisms by which HECTD3 influences cancer cell response to cisplatin.
• To identify proteins interacting with HECTD3 and their role in cisplatin resistance.

Main Methods:

• Yeast two-hybrid analysis to identify HECTD3-interacting proteins.
• Western blotting to assess protein levels (MALT1) in cancer cells under various conditions (HECTD3 depletion/overexpression, cisplatin treatment).
• Apoptosis assays to quantify cell death in response to genetic manipulation and drug treatment.

Main Results:

• HECTD3 directly interacts with mucosa-associated lymphoid tissue 1 (MALT1) via its N-terminal destruction of cyclin domain.
• HECTD3 promotes non-degradative ubiquitination and stabilization of MALT1, rather than its degradation.
• HECTD3 depletion increases cisplatin-induced apoptosis by reducing MALT1 levels, while MALT1 knockdown also sensitizes cells to cisplatin.
• HECTD3 overexpression decreases cisplatin-induced apoptosis, and MALT1 overexpression partially rescues apoptosis in HECTD3-depleted cells.

Conclusions:

• HECTD3 promotes cancer cell survival by stabilizing MALT1.
• The HECTD3-MALT1 axis represents a novel molecular pathway involved in cisplatin resistance.
• Targeting HECTD3 or MALT1 could be a promising strategy for overcoming chemotherapy resistance in cancer therapy.