Systematic Characterization of Mutations Altering Protein Degradation in Human Cancers

Summary: The Ubiquitin-Proteasome System (UPS) is the primary route for selective protein degradation in human cells. The UPS represents an attractive target for novel cancer therapeutics, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes impact UPS function. We implicate transcription factors as important substrates, and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss, and experimentally validated predictions that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Lastly, we identified UPS driver genes associated with patient prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancers and underscores the potential therapeutic utility of targeting the UPS. Data: The data.tar.gz file contains all of the necessary raw data and plots created in the manuscript. The dataset is meant to be used with our code that has been deposited on github as jupyter notebooks (https://github.com/ctokheim/Tokheim_2019). The original_films.zip contains all raw gel pictures shown in the manuscript.研究摘要：泛素-蛋白酶体系统（Ubiquitin-Proteasome System, UPS）是人类细胞内选择性蛋白质降解的核心途径。UPS是新型癌症治疗手段的极具吸引力的靶点，但对于癌症生长至关重要的精准UPS基因及其底物仍未完全明确。本研究依托覆盖9000余例人类肿瘤、涵盖33种癌症类型的多组学数据，发现超过19%的癌症驱动基因会对UPS功能产生影响。我们证实转录因子作为重要底物参与其中，并证明c-Myc的稳定性受CUL3调控。此外，我们开发了深度学习模型deepDegron，用于识别可导致降解基序丢失的突变，并通过实验验证了GATA3与PPM1D的功能获得性截短突变可提升蛋白质稳定性这一预测结论。最后，我们鉴定出与患者预后及肿瘤微环境相关的UPS驱动基因。本研究阐明了UPS失调在人类癌症中的关键作用，并凸显了靶向UPS的潜在治疗价值。 数据说明：data.tar.gz 文件包含本论文手稿中所用的全部原始数据与生成图表。本数据集需配合我们上传至GitHub的代码使用，相关代码以Jupyter笔记本形式存储于https://github.com/ctokheim/Tokheim_2019。original_films.zip 包含手稿中展示的所有原始凝胶电泳图片。