Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss
| Autor: | Tao Wu, Haibiao Xie, William Y. Kim, Xijuan Liu, Lianxin Hu, Marc W. Kirschner, Jeremy M. Simon, Mingjie Li, Albert S. Baldwin, Kan Gong, Jun Wang, Laura E. Herring, Xianming Tan, Cheng Fan, Qing Zhang, Travis S. Ptacek, Giada Zurlo |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cell
Apoptosis Mice SCID Biology urologic and male genital diseases Prolyl Hydroxylases Article law.invention Mice 03 medical and health sciences 0302 clinical medicine Cell Movement Mice Inbred NOD law Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Carcinoma Renal Cell Molecular Biology Cell Proliferation 030304 developmental biology 0303 health sciences Cell growth Cell Cycle Ubiquitination Cancer Cell Biology Prognosis medicine.disease Xenograft Model Antitumor Assays Phenotype Kidney Neoplasms female genital diseases and pregnancy complications Gene Expression Regulation Neoplastic Repressor Proteins Phosphotransferases (Alcohol Group Acceptor) medicine.anatomical_structure Sphingosine kinase 1 Von Hippel-Lindau Tumor Suppressor Protein Cancer research biology.protein Suppressor 030217 neurology & neurosurgery Clear cell Genome-Wide Association Study EGLN1 |
| Zdroj: | Mol Cell |
| ISSN: | 1097-2765 |
| Popis: | Summary von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|