Abstract
Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.
Highlights
These authors contributed : Nadia Habel, Najla El-Hachem, Frédéric SoysouvanhThese authors jointly supervised this work: Corine Bertolotto, Robert BallottiEdited by D
TRIM63, which belongs to the TRIpartite Motif protein family [22], and HERC5, a HECT domain E3 ligase, are endowed with a E3 ligase activity [23] and FBXO32, a F-box only protein is an essential component of the SCFs ubiquitin protein ligase complexes [24]
Compelling research works demonstrated the pivotal role of Microphthalmia-associated transcription factor (MITF) in melanocyte and melanoma through its ability to promote essential biological processes such as differentiation, survival, and proliferation, and to damper motility and invasion [19]
Summary
These authors contributed : Nadia Habel, Najla El-Hachem, Frédéric Soysouvanh. Cutaneous melanoma arises from melanocytes, neural crest-derived cells producing skin pigments. Microphthalmia-associated transcription factor (MITF), the key transcription factor in melanocytes, is known to play a crucial role in melanoma phenotypic switch [12,13,14] and therapy resistance [15,16,17]. MITF was initially described to control differentiation and pigmentation through the regulation of genes involved in melanogenesis [18], MITF was involved in melanoma cell survival and proliferation, while it represses motility and invasive capacities. We performed a comprehensive analysis of the role of FBXO32 in melanoma, showing that it regulates key biological processes and transcriptional programs of melanoma cells through epigenetics mechanisms
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