期刊
ONCOGENE
卷 40, 期 1, 页码 112-126出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-01504-8
关键词
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资金
- Engles Fund for TSC and LAM
- University of Pennsylvania Orphan Disease Center
- LAM Foundation
- NIH NCI [1P01CA120964]
- [DOD-18-1-0592]
- [DOD-17-1-0205]
Tuberous sclerosis complex (TSC) is characterized by tumor development in multiple organs, including renal angiomyolipoma. MITF-A is identified as a transcriptional oncogenic driver of angiomyolipoma tumor development, acting through regulation of CYR61, which plays a crucial role in cell growth and tumor formation.
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by tumor development in multiple organs, including renal angiomyolipoma. Biallelic loss of TSC1 or TSC2 is a known genetic driver of angiomyolipoma development, however, whether an altered transcriptional repertoire contributes to TSC-associated tumorigenesis is unknown. RNA-seq analyses showed that MITF A isoform (MITF-A) was consistently highly expressed in angiomyolipoma, immunohistochemistry showed microphthalmia-associated transcription factor nuclear localization, and Chromatin immuno-Precipitation Sequencing analysis showed that the MITF-A transcriptional start site was highly enriched with H3K27ac marks. Using the angiomyolipoma cell line 621-101, MITF knockout (MITF.KO) and MITF-A overexpressing (MITF.OE) cell lines were generated. MITF.KO cells showed markedly reduced growth and invasion in vitro, and were unable to form xenografted tumors. In contrast, MITF.OE cells grew faster in vitro and as xenografted tumors compared to control cells. RNA-Seq analysis showed that both ID2 and Cysteine-rich angiogenic inducer 61 (CYR61) expression levels were increased in the MITF.OE cells and reduced in the MITF.KO cells, and luciferase assays showed this was due to transcriptional effects. Importantly, CYR61 overexpression rescued MITF.KO cell growth in vitro and tumor growth in vivo. These findings suggest that MITF-A is a transcriptional oncogenic driver of angiomyolipoma tumor development, acting through regulation of CYR61.
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