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CDK1/FBXW7 促进 MLST8 的降解和泛素化，从而抑制肾细胞癌的进展。

CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma.

机构信息

Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

出版信息

Cancer Sci. 2022 Jan;113(1):91-108. doi: 10.1111/cas.15188. Epub 2021 Nov 16.

DOI:10.1111/cas.15188
PMID:34741373
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8748215/
Abstract

Recent studies have reported that MLST8 is upregulated in many malignant tumors. Nevertheless, the underlying molecular mechanism is still unclear. The aim of this work was to investigate how MLST8 contributes to the development and progression of clear cell renal cell carcinoma (ccRCC). MLST8 is an oncogenic protein in the TCGA database and ccRCC clinical specimens. We also ascertain that MLST8 interacts with FBXW7, which was universally regarded as an E3 ubiquitin ligase. MLST8 can be degraded and ubiquitinated by tumor suppressor FBXW7. FBXW7 recognizes a consensus motif (T/S) PXX (S/T/D/E) of MLST8 and triggers MLST8 degradation via the ubiquitin-proteasome pathway. Strikingly, the activated cyclin dependent kinase 1 (CDK1) kinase engages in the MLST8 phosphorylation required for FBXW7-mediated degradation. In vitro, we further prove that MLST8 is an essential mediator of FBXW7 inactivation-induced tumor growth, migration, and invasion. Furthermore, the MLST8 and FBXW7 proteins are negatively correlated in human renal cancer specimens. Our findings suggest that MLST8 is a putative oncogene that functions via interaction with FBXW7, and inhibition MLST8 could be a potential future target in ccRCC treatment.

摘要

最近的研究报告称，MLST8 在许多恶性肿瘤中上调。然而，其潜在的分子机制尚不清楚。本研究旨在探讨 MLST8 如何促进透明细胞肾细胞癌（ccRCC）的发展和进展。MLST8 是 TCGA 数据库和 ccRCC 临床标本中的致癌蛋白。我们还确定 MLST8 与 FBXW7 相互作用，FBXW7 被普遍认为是一种 E3 泛素连接酶。MLST8 可被肿瘤抑制因子 FBXW7 降解和泛素化。FBXW7 识别 MLST8 的共有基序（T/S）PXX（S/T/D/E），并通过泛素蛋白酶体途径触发 MLST8 降解。引人注目的是，激活的周期蛋白依赖性激酶 1（CDK1）激酶参与 FBXW7 介导的降解所需的 MLST8 磷酸化。在体外，我们进一步证明 MLST8 是 FBXW7 失活诱导的肿瘤生长、迁移和侵袭的重要介质。此外，MLST8 和 FBXW7 蛋白在人类肾癌标本中呈负相关。我们的研究结果表明，MLST8 是一种假定的癌基因，通过与 FBXW7 相互作用发挥作用，抑制 MLST8 可能是 ccRCC 治疗的潜在未来靶点。

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