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

Adverse effects of chemotherapies can outweigh the benefits in cancer patients. Various chemotherapeutics are linked to muscle wasting or cachexia, drastically reducing the survival rate of cancer patients. Insights into the molecular basis of chemotherapy-induced cachexia is an unmet need to improve treatment strategies. Here, we demonstrated that Sorafenib- tyrosine kinase inhibitor class of chemotherapeutic agents- induced cachexia. Sorafenib-treated muscle cells show sarcomere disarray, impaired sarcoplasmic reticulum-mediated calcium handling, loss of contractile ability, and reduced mitochondrial oxidative respiratory capacity. To identify the molecular mechanisms underlying Sorafenib-induced cachexia, we performed whole-genome transcriptome profiling or RNA sequencing of muscle cells in response to Sorafenib treatment, compared to DMSO-treated (control) cells. We identified a total of 3030 genes that were downregulated and 2128 genes that were upregulated in Sorafenib-treated cells, as compared to the control. Gene ontology analyses revealed that Sorafenib led to transcriptional downregulation of genes coding for proteins of the sarcomere, sarcoplasmic reticulum, and proteins responsible for muscle contraction, sarcomere organization, and calcium ion handling. Additionally, genes associated with mitochondrial oxidative phosphorylation or electron transport chain were significantly downregulated. In summary, Sorafenib deregulates the transcriptional processes of protein-coding genes associated with sarcomere assembly, calcium ion homeostasis, and mitochondrial oxidative respiration, ultimately leading to impaired muscle function. Overall design: To investigate the effects of Sorafenib treatment on gene expression in muscle cells, we treated murine C2C12-derived myotubes/muscle cells wiht 20 µM Sorafenib for 24 h. Muscle cells treated with 0.1 % DMSO for 24 h were used as the control. After 24 h treatment, total RNA was isolated from the cells. Three independent experiments were performed to generate three samples of DMSO (control)- and Sorafenib-treated muscle cells (N = 3 for both conditions). Global gene expression of Sorafenib-treated cells was comapred to the control (DMSO-treated) cells.