Chemotherapy triggers cachexia by deregulating synergetic function of histone-modifying enzymes

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• Chemotherapy is a primary cancer treatment but causes muscle atrophy (cachexia).
• The NF-κB/MuRF1 pathway is known to induce cachexia.
• Alternative molecular pathways contributing to chemotherapy-induced muscle atrophy remain to be elucidated.

Purpose of the Study:

• To investigate the differential effects of chemotherapeutic drugs on muscle cells.
• To identify novel molecular mechanisms underlying chemotherapy-induced muscle atrophy and cachexia.

Main Methods:

• Utilized mouse satellite stem cell-derived primary muscle cells and C2C12 myotubes.
• Tested daunorubicin, etoposide, and cytarabine.
• Assessed epigenetic, transcriptional, and protein-level changes using ChIP, gene expression profiling, co-immunoprecipitation, and confocal microscopy.
• Evaluated myotube contractile function via electrical stimulation.

Main Results:

• Chemotherapeutic drugs disrupt sarcomere organization and muscle cell contractile ability by reducing MyHC-II expression.
• Drugs impede SETD7 histone methyltransferase chromatin targeting and its synergistic function with p300 histone acetyltransferase.
• Drugs destabilize SENP3, a SUMO deconjugase, which regulates the SETD7-p300 functional axis via a SUMO deconjugation-independent role.

Conclusions:

• Chemotherapeutic drugs alter the SENP3-dependent synergistic action of histone-modifying enzymes in muscle cells.
• A unique epigenetic mechanism targeted by chemotherapeutic drugs triggers chemotherapy-induced cachexia.