Treatment of muscle wasting associated with cancer poses a great challenge in the clinical care and management of cancer patients. Pharmacologically, this aspect of cancer has proven enigmatic, as the molecular details of the protein degradation programs underlying cachexia have not been elucidated. Recent studies have shown that muscle wasting in a number of diseases, including cancer, is principally due to an increase in proteolysis caused by activation of the ubiquitin proteasome system. We identified a cadre of E3 ligases that are transcriptionally regulated by MyoD1, a master regulator of myogenesis, in myoblasts and during the myoblast to myotube transition using genomic transcription factor binding (ChIP-on-chip) analyses. We hypothesize that these E3 ligases normally function in muscle homeostasis and that muscle wasting in cancer may be due in part to inappropriate, sustained activation of muscle-specific E3 ligases. Thus, these E3 ligases (and their regulators) could represent viable drug targets in the treatment of muscle wasting in cancer and other diseases. Here, we will explore this hypothesis in two specific aims. First, we will conduct a proteomic screen for substrates of Rnf11, a member of the group of E3 ligases previously identified in our MyoD1 genomic screen, in fully differentiated C2C12 myotubes using dexamethasone treatment as a tissue culture model of muscle atrophy. Second, we will attempt to validate ubiquitylation of these putative substrates by the Rnf11 E3 ligase in vitro and in our tissue culture model of muscle atrophy. This Proposal is designed to develop innovative and previously unexplored approaches to combat muscle wasting associated with cancer and therefore presents novel possibilities for its clinical management.
Cachexia is a clinically debilitating feature of many diseases including cancer. Current research suggests that it mainly occurs through an increase in proteolysis caused by the activation of the ubiquitin-proteasome system. Proteomic screens identifying substrates of muscle specific E3 ligases will provide insight into drug development for the clinical management of muscle wasting associated with cancer.
|Malonis, Ryan J; Fu, Wenxiang; Jelcic, Mark J et al. (2017) RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor ? signaling. J Biol Chem 292:7435-7451|