Description:
<jats:title>Summary</jats:title><jats:p><jats:styled-content style="fixed-case">FBXW</jats:styled-content>7 is well characterized as a tumor suppressor in many human cancers including melanoma; however, the mechanisms of tumor‐suppressive function have not been fully elucidated. We leveraged two distinct <jats:styled-content style="fixed-case">RNA</jats:styled-content> sequencing datasets: human melanoma cell lines (<jats:italic>n </jats:italic>=<jats:italic> </jats:italic>10) with control versus silenced <jats:italic><jats:styled-content style="fixed-case">FBXW</jats:styled-content>7</jats:italic> and a cohort of human melanoma tumor samples (<jats:italic>n </jats:italic>=<jats:italic> </jats:italic>51) to define the transcriptomic fingerprint regulated by <jats:styled-content style="fixed-case">FBXW</jats:styled-content>7. Here, we report that loss of <jats:styled-content style="fixed-case">FBXW</jats:styled-content>7 enhances a mitochondrial gene transcriptional program that is dependent on <jats:styled-content style="fixed-case">MITF</jats:styled-content> in human melanoma and confers poor patient outcomes. <jats:styled-content style="fixed-case">MITF</jats:styled-content> is a lineage‐specific master regulator of melanocytes and together with <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1alpha is a marker for melanoma subtypes with dependence for mitochondrial oxidative metabolism. We found that inactivation of <jats:styled-content style="fixed-case">FBXW</jats:styled-content>7 elevates <jats:styled-content style="fixed-case">MITF</jats:styled-content> protein levels in melanoma cells. In vitro studies examining loss of <jats:styled-content style="fixed-case">FBXW</jats:styled-content>7 and <jats:styled-content style="fixed-case">MITF</jats:styled-content> alone or in combination showed that <jats:styled-content style="fixed-case">FBXW</jats:styled-content>7 is an upstream regulator for the <jats:styled-content style="fixed-case">MITF</jats:styled-content>/<jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1 signaling.</jats:p>