Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes

Area of Science:

• Molecular biology
• Cancer therapy
• Muscle physiology

Background:

• Chemotherapy often causes muscle wasting (cachexia), impacting patient treatment.
• Understanding the molecular mechanisms of chemotherapy-induced cachexia is crucial for developing better therapies.

Purpose of the Study:

• To investigate the molecular basis of cachexia induced by Sorafenib, a tyrosine kinase inhibitor (TKI).
• To identify the specific mechanisms by which Sorafenib affects muscle cells.

Main Methods:

• System-wide transcriptional and proteostasis analyses in muscle cells treated with Sorafenib.
• Investigated the role of epigenetic modifications, specifically H3K4 methylation and the SET1A complex.

Main Results:

• Sorafenib induced cachexia by altering global transcription and proteostasis in muscle cells.
• Sorafenib reduced H3K4 methylation on muscle-specific genes by inhibiting SET1A, leading to transcriptional disruption.
• This disruption affected sarcomere assembly, calcium homeostasis, and mitochondrial respiration, compromising muscle function.
• Other TKIs like Nilotinib and Imatinib did not cause similar effects.

Conclusions:

• Identified a novel transcriptional mechanism for Sorafenib-induced cachexia involving epigenetic dysregulation.
• Findings suggest potential therapeutic strategies to mitigate Sorafenib-induced muscle wasting.