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

ABSTRACT: Chemotherapeutics used in cancer therapy are often linked to muscle wasting or cachexia. Insights into the molecular basis of chemotherapy-induced cachexia is essential to improve treatment strategies. Here, we demonstrated that Sorafenib-tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents-induced cachexia. System-wide analyses revealed that Sorafenib alters the global transcriptional program and proteostasis in muscle cells. Mechanistically, Sorafenib treatment reduced active epigenetic mark H3K4 methylation on distinct muscle-specific genes by impeding chromatin association of SET1A-catalytic component of the SET1/MLL histone methyltransferase complex. This mechanism favored transcriptional disorientation that led to disrupted sarcomere assembly, calcium homeostasis and mito

SUBMITTER: Khan B 

PROVIDER: S-EPMC11462028 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature