Dataset Information

Nonparametric Analysis of Thermal Proteome Profiles Reveals Novel Drug-binding Proteins.

ABSTRACT: Detecting the targets of drugs and other molecules in intact cellular contexts is a major objective in drug discovery and in biology more broadly. Thermal proteome profiling (TPP) pursues this aim at proteome-wide scale by inferring target engagement from its effects on temperature-dependent protein denaturation. However, a key challenge of TPP is the statistical analysis of the measured melting curves with controlled false discovery rates at high proteome coverage and detection power. We present nonparametric analysis of response curves (NPARC), a statistical method for TPP based on functional data analysis and nonlinear regression. We evaluate NPARC on five independent TPP data sets and observe that it is able to detect subtle changes in any region of the melting curves, reliably detects the known targets, and outperforms a melting point-centric, single-parameter fitting approach in terms of specificity and sensitivity. NPARC can be combined with established analysis of variance (ANOVA) statistics and enables flexible, factorial experimental designs and replication levels. An open source software implementation of NPARC is provided.

SUBMITTER: Childs D

PROVIDER: S-EPMC6885700 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Nonparametric Analysis of Thermal Proteome Profiles Reveals Novel Drug-binding Proteins.

Childs Dorothee D Bach Karsten K Franken Holger H Anders Simon S Kurzawa Nils N Bantscheff Marcus M Savitski Mikhail M MM Huber Wolfgang W

Molecular & cellular proteomics : MCP 20191003 12

Detecting the targets of drugs and other molecules in intact cellular contexts is a major objective in drug discovery and in biology more broadly. Thermal proteome profiling (TPP) pursues this aim at proteome-wide scale by inferring target engagement from its effects on temperature-dependent protein denaturation. However, a key challenge of TPP is the statistical analysis of the measured melting curves with controlled false discovery rates at high proteome coverage and detection power. We presen ...[more]

PMID: 31582558

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Project description:BackgroundAccumulating evidence indicates importance of RNA regulation in cancer. This includes events such as splicing, translation, and regulation of noncoding RNAs, functions which are governed by RNA binding proteins (RBPs).AimsTo find which RBPs could be relevant for prostate cancer, we performed systematic screening of RBP expression in clinical prostate cancer.Methods and resultsWe interrogated four proteome-wide proteomics datasets including tumor samples of primary, castration resistant, and metastatic prostate cancer. We found that, while the majority of RBPs are expressed but not significantly altered during prostate cancer development and progression, expression of several RBPs increases in advanced disease. Interestingly, most of the differentially expressed RBPs are not targets of differential posttranscriptional phosphorylation during disease progression. The RBPs undergoing expression changes have functions in, especially, poly(A)-RNA binding, nucleocytoplasmic transport, and cellular stress responses, suggesting that these may play a role in formation of castration resistance. Pathway analyzes indicate that increased ribosome production and chromatin-related functions of RBPs are also linked to castration resistant and metastatic prostate cancers. We selected a group of differentially expressed RBPs and studied their role in cultured prostate cancer cells. With siRNA screens, several of these were indicated in survival (DDX6, EIF4A3, PABPN1), growth (e.g., EIF5A, HNRNPH2, LRRC47, and NVL), and migration (e.g., NOL3 and SLTM) of prostate cancer cells. Our analyzes further show that RRP9, a U3 small nucleolar protein essential for ribosome formation, undergoes changes at protein level during metastasis in prostate cancer.ConclusionIn this work, we recognized significant molecular alterations in RBP profiles during development and evolution of prostate cancer. Our study further indicates several functionally significant RBPs warranting further investigation for their functions and possible targetability in prostate cancer.

Dataset Information

Nonparametric Analysis of Thermal Proteome Profiles Reveals Novel Drug-binding Proteins.

Publications

Nonparametric Analysis of Thermal Proteome Profiles Reveals Novel Drug-binding Proteins.

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