HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

Abstract

Significance Proinflammatory diseases, such as cancer, AIDS, and chronic obstructive pulmonary diseases, are often associated with a progressive loss of skeletal muscle tissue, a syndrome also known as cachexia. Cytokines trigger muscle loss by activating downstream effector pathways, including the ones driven by STAT3 protein. Although high levels of STAT3 protein are required for the onset of muscle wasting, the mechanisms modulating STAT3 expression in cachectic muscles remain elusive. Here we identify the RNA-binding protein HuR and its ability to interfere with miR-330 action as a key promoter of STAT3 mRNA translation. Our work identifies the competition between HuR and miR-330 as a mechanism that could be targeted to design novel anticachexia therapies. Debilitating cancer-induced muscle wasting, a syndrome known as cachexia, is lethal. Here we report a posttranscriptional pathway involving the RNA-binding protein HuR as a key player in the onset of this syndrome. Under these conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 (signal transducer and activator of transcription 3) mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330 (microRNA 330)–mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3′untranslated region (UTR) located within the vicinity of the miR-330 seed element. Even though the binding sites of HuR and miR-330 do not overlap, the recruitment of either one of them to the STAT3-3′UTR negatively impacts the binding and the function of the other factor. Therefore, together, our data establish the competitive interplay between HuR and miR-330 as a mechanism via which muscle fibers modulate, in part, STAT3 expression to determine their fate in response to promoters of muscle wasting.