Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.,Molecular Cell

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Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-01-29 , DOI: 10.1016/j.molcel.2020.01.009
Xijuan Liu ₁ , Jeremy M Simon ₂ , Haibiao Xie ₃ , Lianxin Hu ₄ , Jun Wang ₁ , Giada Zurlo ₄ , Cheng Fan ₁ , Travis S Ptacek ₅ , Laura Herring ₆ , Xianming Tan ₁ , Mingjie Li ₄ , Albert S Baldwin ₁ , William Y Kim ₁ , Tao Wu ₇ , Marc W Kirschner ₇ , Kan Gong ₃ , Qing Zhang ₈

Affiliation

Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Urology, Peking University First Hospital, Beijing, China.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Proteomics Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

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.

中文翻译：

全基因组筛选确定SFMBT1是VHL丢失的癌症的致癌驱动因素。

von Hippel-Lindau（VHL）是透明细胞肾细胞癌（ccRCC）中的关键肿瘤抑制因子。除了缺氧诱导因子2α（HIF2α）之外，在VHL丢失的下游ccRCC中确定其他治疗靶标也很重要。通过执行全基因组筛选，我们确定了具有四个恶性脑肿瘤域1（SFMBT1）的Scm样蛋白作为候选pVHL靶标。SFMBT1被认为是转录阻遏物，但其在癌症中的作用仍不清楚。VHL功能丧失突变的ccRCC患者显示SFMBT1蛋白水平升高。EglN1对脯氨酸残基651的SFMBT1羟化作用介导了其泛素化和pVHL降解。SFMBT1的消耗在体外消除了ccRCC细胞增殖，并在体内抑制了原位肿瘤的生长。ChIP-seq，RNA-seq，并且患者预后确定鞘氨醇激酶1（SPHK1）是促成其致癌表型的关键SFMBT1靶基因。因此，pVHL-SFMBT1-SPHK1轴可作为ccRCC的潜在治疗途径。

更新日期：2020-02-04

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