ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer

Significance Statement ONECUT2 (OC2) is a master transcription factor that alters lineage identity by activating gene networks associated with both neuroendocrine prostate cancer and prostate adenocarcinoma. A small molecule inhibitor of OC2 represses the lineage plasticity program activated by enzalutamide, suggesting OC2 inhibition as a novel therapeutic strategy to prevent emergence of treatment-resistant variants. Graphic Abstract Androgen receptor-(AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

[1]  Xiaolin Zhu,et al.  The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer , 2023, Cancer research.

[2]  Ekta Khurana,et al.  ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer , 2023, Science advances.

[3]  Lara E Sucheston-Campbell,et al.  African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A , 2023, Cancer research communications.

[4]  Joel A. Yates,et al.  Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity , 2022, Nature Communications.

[5]  L. Mazutis,et al.  Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling , 2022, Science.

[6]  A. Zoubeidi,et al.  ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer , 2022, Nature Communications.

[7]  D. Di Vizio,et al.  Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis , 2022, Nature Communications.

[8]  A. Chinnaiyan,et al.  Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer , 2021, Nature.

[9]  Jana M. Braunger,et al.  decoupleR: ensemble of computational methods to infer biological activities from omics data , 2021, bioRxiv.

[10]  Joshua D Mentzer,et al.  Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer , 2021, Nature Communications.

[11]  H. G. van der Poel,et al.  Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence , 2021, medRxiv.

[12]  H. G. van der Poel,et al.  An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer , 2021, Nature Cell Biology.

[13]  S. Balk,et al.  Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer , 2021, Clinical Cancer Research.

[14]  Christian H. Holland,et al.  Corrigendum: Benchmark and integration of resources for the estimation of human transcription factor activities. , 2021, Genome research.

[15]  P. Nelson,et al.  Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling , 2021, Nature communications.

[16]  H. Beltran,et al.  Clinical and Biological Features of Neuroendocrine Prostate Cancer , 2021, Current Oncology Reports.

[17]  T. H. van der Kwast,et al.  Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression , 2021, Nature Cell Biology.

[18]  Wei Xue,et al.  Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer , 2020, Communications biology.

[19]  Henry W. Long,et al.  Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer , 2020, Nature Communications.

[20]  Xinghua Pan,et al.  Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing , 2020, Molecular cancer.

[21]  D. Pe’er,et al.  Regenerative potential of prostate luminal cells revealed by single-cell analysis , 2020, Science.

[22]  C. Mason,et al.  Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation , 2020, Cancer cell.

[23]  S. Mirarab,et al.  Sequence Analysis , 2020, Encyclopedia of Bioinformatics and Computational Biology.

[24]  M. Freeman,et al.  Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential , 2020, BMC Cancer.

[25]  P. Nelson,et al.  Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. , 2019, The Journal of clinical investigation.

[26]  M. Loda,et al.  The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance , 2019, Clinical Cancer Research.

[27]  Dan Tenenbaum,et al.  Peak calling by Sparse Enrichment Analysis for CUT&RUN chromatin profiling , 2019, Epigenetics & Chromatin.

[28]  T. Graeber,et al.  Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies. , 2019, Cancer cell.

[29]  Anshul Kundaje,et al.  The ENCODE Blacklist: Identification of Problematic Regions of the Genome , 2019, Scientific Reports.

[30]  T. H. van der Kwast,et al.  ONECUT2 is a driver of neuroendocrine prostate cancer , 2019, Nature Communications.

[31]  Paul J. Hoffman,et al.  Comprehensive Integration of Single-Cell Data , 2018, Cell.

[32]  Simon G. Coetzee,et al.  ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis , 2018, Nature Medicine.

[33]  L. Hennighausen,et al.  Progressing super-enhancer landscape during mammary differentiation controls tissue-specific gene regulation , 2018, Nucleic acids research.

[34]  V. Kepe,et al.  Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging , 2018, The Journal of Biological Chemistry.

[35]  K. Sheu,et al.  A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers. , 2018, Cell reports.

[36]  Zev J. Gartner,et al.  DoubletFinder: Doublet detection in single-cell RNA sequencing data using artificial nearest neighbors , 2018, bioRxiv.

[37]  J. Sáez-Rodríguez,et al.  Benchmark and integration of resources for the estimation of human transcription factor activities , 2018, bioRxiv.

[38]  Ignacio J. Tripodi,et al.  Detecting Differential Transcription Factor Activity from ATAC-Seq Data , 2018, bioRxiv.

[39]  Brent S. Pedersen,et al.  GIGGLE: a search engine for large-scale integrated genome analysis , 2017, Nature Methods.

[40]  Janet Iwasa,et al.  Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes , 2017, Nature Reviews Molecular Cell Biology.

[41]  Satyaki Sengupta,et al.  Super-Enhancer-Driven Transcriptional Dependencies in Cancer. , 2017, Trends in cancer.

[42]  Kin Chung Lam,et al.  High-resolution TADs reveal DNA sequences underlying genome organization in flies , 2017, Nature Communications.

[43]  C. Collins,et al.  Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance , 2017, Oncotarget.

[44]  M. Rubin,et al.  SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer , 2017, Science.

[45]  Neva C. Durand,et al.  Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. , 2016, Cell systems.

[46]  Fidel Ramírez,et al.  deepTools2: a next generation web server for deep-sequencing data analysis , 2016, Nucleic Acids Res..

[47]  A. Mroz,et al.  The role of glucuronidation in drug resistance. , 2016, Pharmacology & therapeutics.

[48]  Matteo Benelli,et al.  Divergent clonal evolution of castration resistant neuroendocrine prostate cancer , 2016, Nature Medicine.

[49]  M. Gleave,et al.  The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors , 2015, International journal of cancer.

[50]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[51]  Howard Y. Chang,et al.  ATAC‐seq: A Method for Assaying Chromatin Accessibility Genome‐Wide , 2015, Current protocols in molecular biology.

[52]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[53]  D. Zheng,et al.  Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade , 2013, Cell.

[54]  N. Kyprianou,et al.  Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression , 2013, Translational andrology and urology.

[55]  R. Cardiff,et al.  ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer , 2013, Proceedings of the National Academy of Sciences.

[56]  David A. Orlando,et al.  Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes , 2013, Cell.

[57]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[58]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[59]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[60]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[61]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[62]  Matthew D. Wilkerson,et al.  ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking , 2010, Bioinform..

[63]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[64]  P. Kantoff,et al.  Androgen receptor mediates the expression of UDP‐glucuronosyltransferase 2 B15 and B17 genes , 2008, The Prostate.

[65]  O. Barbier,et al.  Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[66]  Olivier Barbier,et al.  UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells* , 2007, Journal of Biological Chemistry.

[67]  S. Bonassi,et al.  Normalization of low-density microarray using external spike-in controls: analysis of macrophage cell lines expression profile , 2007, BMC Genomics.

[68]  Hamid Bolouri,et al.  A data integration methodology for systems biology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Mesirov,et al.  From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005 .

[70]  M. Rubin,et al.  The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer. , 2017, Cancer discovery.

[71]  C. Collins,et al.  SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition. , 2017, European urology.

[72]  David C. Smith,et al.  Integrative Clinical Genomics of Advanced Prostate Cancer Graphical , 2015 .

[73]  J. Mesirov,et al.  The Molecular Signatures Database (MSigDB) hallmark gene set collection. , 2015, Cell systems.

[74]  T. Uchiumi,et al.  Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression , 2010, Oncogene.

[75]  J. Castle,et al.  expression data: the tissue distribution of human pathways , 2006 .

[76]  C. Lottaz,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

[77]  I. Amit,et al.  Supporting Online Material Materials and Methods Som Text Comprehensive Mapping of Long-range Interactions Reveals Folding Principles of the Human Genome , 2022 .