Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
Pigment Cell Melanoma Res. 2018 Sep;31(5):636-640. doi: 10.1111/pcmr.12704. Epub 2018 Apr 29.
FBXW7 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 FBXW7 and a cohort of human melanoma tumor samples (n = 51) to define the transcriptomic fingerprint regulated by FBXW7. Here, we report that loss of FBXW7 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 FBXW7 elevates MITF protein levels in melanoma cells. In vitro studies examining loss of FBXW7 and MITF alone or in combination showed that FBXW7 is an upstream regulator for the MITF/PGC-1 signaling.
FBXW7 在包括黑色素瘤在内的许多人类癌症中被很好地描述为肿瘤抑制因子；然而，其肿瘤抑制功能的机制尚未完全阐明。我们利用了两个不同的 RNA 测序数据集：对照和沉默 FBXW7 的人黑色素瘤细胞系（n=10）和人黑色素瘤肿瘤样本队列（n=51），以定义 FBXW7 调节的转录组特征。在这里，我们报告说，FBXW7 的缺失增强了一个依赖于 MITF 的线粒体基因转录程序，这在人类黑色素瘤中导致了不良的患者预后。MITF 是黑素细胞的特异性主调控因子，与 PGC-1alpha 一起是依赖线粒体氧化代谢的黑色素瘤亚型的标志物。我们发现 FBXW7 的失活会提高黑色素瘤细胞中的 MITF 蛋白水平。体外研究检查了 FBXW7 和 MITF 的单独失活或联合失活，表明 FBXW7 是 MITF/PGC-1 信号的上游调节因子。
