FBXW 7 regulates a mitochondrial transcription program by modulating MITF

Summary FBXW 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 RNA sequencing datasets: human melanoma cell lines ( n  =   10) with control versus silenced FBXW 7 and a cohort of human melanoma tumor samples ( n  =   51) to define the transcriptomic fingerprint regulated by FBXW 7. Here, we report that loss of FBXW 7 enhances a mitochondrial gene transcriptional program that is dependent on MITF in human melanoma and confers poor patient outcomes. MITF is a lineage‐specific master regulator of melanocytes and together with PGC ‐1alpha is a marker for melanoma subtypes with dependence for mitochondrial oxidative metabolism. We found that inactivation of FBXW 7 elevates MITF protein levels in melanoma cells. In vitro studies examining loss of FBXW 7 and MITF alone or in combination showed that FBXW 7 is an upstream regulator for the MITF / PGC ‐1 signaling.