@article{e7deefaf675f417c87bb1b6ef010ee3c,
title = "Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss",
abstract = "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.",
keywords = "SFMBT1, SPHK1, ccRCC, pVHL",
author = "Xijuan Liu and Simon, {Jeremy M.} and Haibiao Xie and Lianxin Hu and Jun Wang and Giada Zurlo and Cheng Fan and Ptacek, {Travis S.} and Laura Herring and Xianming Tan and Mingjie Li and Baldwin, {Albert S.} and Kim, {William Y.} and Tao Wu and Kirschner, {Marc W.} and Kan Gong and Qing Zhang",
note = "Funding Information: We thank Dr. William G. Kaelin, Jr., for his support as the initial screening was performed by Q.Z. in Dr. Kaelin{\textquoteright}s lab in collaboration with Dr. Kirschner{\textquoteright}s lab with support from NCI R01 CA068490 . We thank UNC LCCC Tissue Procurement Facility, UNC Animal Studies Core, and UNC Translational Pathology Laboratory for excellent help. This work was supported in part by the National Cancer Institute (Q.Z., R01CA211732 and R21CA223675 ) and Cancer Prevention and Research Institute of Texas (CPRIT, RP190058 to Q.Z.). J.M.S. and T.S.P. were supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development ( U54HD079124 ) and NINDS ( P30NS045892 ). Q.Z. is an American Cancer Society Research Scholar, CPRIT Scholar in Cancer Research, V Scholar, Kimmel Scholar, Susan G. Komen Career Catalyst awardee, and Mary Kay Foundation awardee. Q.Z. is also supported by Kidney Cancer Research Alliance (KCCure). This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Funding Information: We thank Dr. William G. Kaelin, Jr. for his support as the initial screening was performed by Q.Z. in Dr. Kaelin's lab in collaboration with Dr. Kirschner's lab with support from NCI R01 CA068490. We thank UNC LCCC Tissue Procurement Facility, UNC Animal Studies Core, and UNC Translational Pathology Laboratory for excellent help. This work was supported in part by the National Cancer Institute (Q.Z. R01CA211732 and R21CA223675) and Cancer Prevention and Research Institute of Texas (CPRIT, RP190058 to Q.Z.). J.M.S. and T.S.P. were supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124) and NINDS (P30NS045892). Q.Z. is an American Cancer Society Research Scholar, CPRIT Scholar in Cancer Research, V Scholar, Kimmel Scholar, Susan G. Komen Career Catalyst awardee, and Mary Kay Foundation awardee. Q.Z. is also supported by Kidney Cancer Research Alliance (KCCure). This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Q.Z. T.W. and M.W.K. conceived the project. X.L. and Q.Z. designed, performed and interpreted experiments, and co-wrote the paper. J.M.S. and T.S.P. contributed to RNA, ChIP-seq bioinformatics analyses. J.M.S. also helped with the paper editing. H.X. M.L. and K.G. provided critical guidance and helps on IHC and TMA. L.H. contributed to in vitro decarboxylation assay. J.W. performed some cell proliferation and anchorage-independent growth assay. G.Z. provided purified proteins. F.C. contributed to patient prognosis data analysis. X.T. contributed to statistical analysis. L.H. helped with LC-MS/MS analysis. T.W. and M.W.K. contributed to genome-wide screening. W.Y.K. provided ccRCC mouse model. A.S.B. helped with guidance for critical experiments and paper writing. The authors declare no competing interests.",
year = "2020",
month = mar,
day = "19",
doi = "10.1016/j.molcel.2020.01.009",
language = "English (US)",
volume = "77",
pages = "1294--1306.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}