Cancer cachexia (CC) is a multifactorial syndrome characterized by a significant reduction in body weight that is predominantly caused by the loss of skeletal muscle and adipose tissue. Although the ill effects of cachexia are well known, the condition has been largely overlooked, in part due to its complex etiology, heterogeneity in mediators, and the involvement of diverse signaling pathways. For a long time, inflammatory factors have been the focus when developing therapeutics for the treatment of CC. Despite promising pre-clinical results, they have not yet advanced to the clinic. Developing new therapies requires a comprehensive understanding of how deregulated signaling leads to catabolic gene expression that underlies muscle wasting. Here, we review CC-associated signaling pathways and the transcriptional cascade triggered by inflammatory cytokines. Further, we highlight epigenetic factors involved in the transcription of catabolic genes in muscle wasting. We conclude with reflections on the directions that might pave the way for new therapeutic approaches to treat CC.
Histone acetylation and methylation are epigenetic modifications that are dynamically regulated by chromatin modifiers to precisely regulate gene expression. However, the interplay by which histone modifications are synchronized to coordinate cellular differentiation is not fully understood. In this study, we demonstrate a relationship between BRD4, a reader of acetylation marks, and G9a, a writer of methylation marks in the regulation of myogenic differentiation. Using loss- and gain-of-function studies, as well as a pharmacological inhibition of its activity, we examined the mechanism by which BRD4 regulates myogenesis. Transcriptomic analysis using RNA sequencing revealed that a number of myogenic differentiation genes are downregulated in Brd4-depleted cells. Interestingly, some of these genes were upregulated upon G9a knockdown, indicating that BRD4 and G9a play opposing roles in the control of myogenic gene expression. Remarkably, the differentiation defect caused by Brd4 knockdown was rescued by inhibition of G9a methyltransferase activity. These findings demonstrate that the absence of BRD4 results in the upregulation of G9a activity and consequently impaired myogenic differentiation. Collectively, our study identifies an interdependence between BRD4 and G9a for the precise control of transcriptional outputs to regulate myogenesis.
BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analyzed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumor progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumor growth, but strikingly promotes metastasis in vivo. Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. Our work unveils isoform-specific functions of BRD4 and demonstrates that BRD4-S functions as a gatekeeper to constrain the full oncogenic potential of BRD4-L.
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