Complementary analysis of proteome-wide proteomics reveals changes in RNA binding protein-profiles during prostate cancer progression.

BACKGROUND Accumulating 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). AIMS To find which RBPs could be relevant for prostate cancer, we performed systematic screening of RBP expression in clinical prostate cancer. METHODS AND RESULTS We 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. CONCLUSION In 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.

[1]  D. Qi,et al.  RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway , 2022, Cell Communication and Signaling.

[2]  Y. Minami,et al.  c-Src–mediated phosphorylation and activation of kinesin KIF1C promotes elongation of invadopodia in cancer cells , 2022, The Journal of biological chemistry.

[3]  P. Xie,et al.  Neddylation modification of the U3 snoRNA-binding protein RRP9 by Smurf1 promotes tumorigenesis , 2021, The Journal of biological chemistry.

[4]  L. Latonen,et al.  Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes , 2021, Cancers.

[5]  Jaana M. Hartikainen,et al.  Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells , 2021, Oncogene.

[6]  Li Yang,et al.  Effect of eukaryotic translation initiation factor 4A3 in malignant tumors , 2021, Oncology letters.

[7]  L. Latonen,et al.  Androgen-Driven Fusion Genes and Chimeric Transcripts in Prostate Cancer , 2021, Frontiers in Cell and Developmental Biology.

[8]  T. H. van der Kwast,et al.  Prostate cancer , 2021, Nature Reviews Disease Primers.

[9]  Xian Du,et al.  An emerging role of chromatin-interacting RNA-binding proteins in transcription regulation. , 2020, Essays in biochemistry.

[10]  Levi Waldron,et al.  HGNChelper: identification and correction of invalid gene symbols for human and mouse , 2020, bioRxiv.

[11]  E. Markert,et al.  2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer , 2020, Nature Communications.

[12]  R. Irizarry.  ggplot2 , 2019, Introduction to Data Science.

[13]  P. Sorensen,et al.  Pharmacological systems analysis defines EIF4A3 functions in cell-cycle and RNA stress granule formation , 2019, Communications Biology.

[14]  Natalie S. Fox,et al.  The Proteogenomic Landscape of Curable Prostate Cancer. , 2019, Cancer cell.

[15]  Chunling Yuan,et al.  Systematic Analysis of Gene Expression Alteration and Co-Expression Network of Eukaryotic Initiation Factor 4A-3 in Cancer , 2018, Journal of Cancer.

[16]  M. Nykter,et al.  Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression , 2018, Nature Communications.

[17]  M. Rubin,et al.  The Genomics of Prostate Cancer: emerging understanding with technologic advances , 2018, Modern Pathology.

[18]  A. Flores-Morales,et al.  Quantitative Mass Spectrometry-Based Proteomic Profiling for Precision Medicine in Prostate Cancer , 2017, Front. Oncol..

[19]  K. Fukuda,et al.  Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors. , 2017, ACS medicinal chemistry letters.

[20]  A. Ridley,et al.  The RNA‐binding protein LARP4 regulates cancer cell migration and invasion , 2016, Cytoskeleton.

[21]  Roland Eils,et al.  Complex heatmaps reveal patterns and correlations in multidimensional genomic data , 2016, Bioinform..

[22]  Evan O. Paull,et al.  Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer , 2016, Cell.

[23]  Ronald J. Moore,et al.  Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer , 2016, Cell.

[24]  Pär Stattin,et al.  The Proteome of Primary Prostate Cancer. , 2016, European urology.

[25]  Michael L. Gatza,et al.  Proteogenomics connects somatic mutations to signaling in breast cancer , 2016, Nature.

[26]  Xintao Wei,et al.  Resources for the comprehensive discovery of functional RNA elements , 2015, bioRxiv.

[27]  V. Arora,et al.  Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer , 2015, Nature Reviews Cancer.

[28]  S. Blagden,et al.  The La-Related Proteins, a Family with Connections to Cancer , 2015, Biomolecules.

[29]  M. Mathews,et al.  The translation factor eIF5A and human cancer. , 2015, Biochimica et biophysica acta.

[30]  Peter Hoffmann,et al.  Proteomic developments in the analysis of formalin-fixed tissue. , 2015, Biochimica et biophysica acta.

[31]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[32]  S. Gerstberger,et al.  A census of human RNA-binding proteins , 2014, Nature Reviews Genetics.

[33]  Jeffrey R. Whiteaker,et al.  Proteogenomic characterization of human colon and rectal cancer , 2014, Nature.

[34]  Jinzhong Lin,et al.  Structural and functional analysis of the U3 snoRNA binding protein Rrp9. , 2013, RNA.

[35]  Norman E. Davey,et al.  Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins , 2012, Cell.

[36]  M. Sadar,et al.  FUS/TLS Is a Co-Activator of Androgen Receptor in Prostate Cancer Cells , 2011, PloS one.

[37]  John T. Wei,et al.  Transcriptome Sequencing Identifies PCAT-1, a Novel lincRNA Implicated in Prostate Cancer Progression , 2011, Nature biotechnology.

[38]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[39]  Kai-Wei Chang,et al.  RNA-binding proteins in human genetic disease. , 2008, Trends in genetics : TIG.

[40]  V. Vasiliou,et al.  Polymorphisms of Human Aldehyde Dehydrogenases , 2000, Pharmacology.

[41]  C. Pellizas,et al.  Differential expression of Low density lipoprotein Receptor-related Protein 1 (LRP-1) and matrix metalloproteinase-9 (MMP-9) in prostate gland: From normal to malignant lesions. , 2017, Pathology, research and practice.

[42]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.