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FBXW 7 regulates a mitochondrial transcription program by modulating MITF
Author(s) -
Abbate Franco,
Badal Brateil,
Mendelson Karen,
Aydin Iraz T.,
Serasinghe Madhavika N.,
Iqbal Ramiz,
Mohammed Jarvier N.,
Solovyov Alexander,
Greenbaum Benjamin D.,
Chipuk Jerry E.,
Celebi Julide T.
Publication year - 2018
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12704
Subject(s) - microphthalmia associated transcription factor , transcription factor , microbiology and biotechnology , transcription (linguistics) , chemistry , biology , biochemistry , gene , linguistics , philosophy
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.