Advertisement

Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes

  • Juan M. Jiménez-Vacas
    Correspondence
    Reprint requests: Juan M. Jiménez-Vacas and Raúl M. Luque. Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), IMIBIC Building. Av. Menéndez Pidal s/n. 14004-Córdoba, Spain.
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Antonio J. Montero-Hidalgo
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Enrique Gómez-Gómez
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Urology Service, HURS/IMIBIC, Cordoba, Spain
    Search for articles by this author
  • Prudencio Sáez-Martínez
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Antonio C. Fuentes-Fayos
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Adrià Closa
    Affiliations
    The John Curtin School of Medical Research, Australian National University, Canberra, Australia

    EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia
    Search for articles by this author
  • Teresa González-Serrano
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Anatomical Pathology Service, HURS, Cordoba, Spain
    Search for articles by this author
  • Ana Martínez-López
    Affiliations
    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Anatomical Pathology Service, HURS, Cordoba, Spain
    Search for articles by this author
  • Rafael Sánchez-Sánchez
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Anatomical Pathology Service, HURS, Cordoba, Spain
    Search for articles by this author
  • Pedro P. López-Casas
    Affiliations
    Prostate Cancer Clinical Research Unit, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
    Search for articles by this author
  • André Sarmento-Cabral
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • David Olmos
    Affiliations
    Prostate Cancer Clinical Research Unit, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
    Search for articles by this author
  • Eduardo Eyras
    Affiliations
    The John Curtin School of Medical Research, Australian National University, Canberra, Australia

    EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia

    Catalan Institution for Research and Advanced Studies. Barcelona, Spain

    Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
    Search for articles by this author
  • Justo P. Castaño
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Manuel D. Gahete
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
  • Raul M. Luque
    Correspondence
    Reprint requests: Juan M. Jiménez-Vacas and Raúl M. Luque. Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), IMIBIC Building. Av. Menéndez Pidal s/n. 14004-Córdoba, Spain.
    Affiliations
    Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain

    Hospital Universitario Reina Sofía (HURS), Cordoba, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
    Search for articles by this author
Open AccessPublished:September 08, 2022DOI:https://doi.org/10.1016/j.trsl.2022.08.016

      Abstract

      Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients’ outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.

      Graphical Abstract

      Abbreviation:

      AR (androgen receptor), BPH (benign prostatic hyperplasia), FDR (false discovery rate), FFPE (formalin-fixed, paraffin-embedded), GS (gleason score), IHC (immunohistochemistry), IPA (ingenuity pathway analysis), MD-PCa (moderately differentiated prostate cancer), N-TAR (non-tumor adjacent region), PCa (prostate cancer), PD-PCa (poorly differentiated prostate cancer), PI3K (phosphoInositide 3-kinase), PIN (prostatic intraepithelial neoplasia), RBM22 (RNA binding motif protein 22), RRM (rna recognition motif), TRAMP (transgenic adenocarcinoma of mouse prostate model)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bray F
        • Ferlay J
        • Soerjomataram I
        • Siegel RL
        • Torre LA
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Tolkach Y
        • Kristiansen G
        The heterogeneity of prostate cancer: a practical approach.
        Pathobiology. 2018; 85: 108-116
        • Sandhu S
        • Moore CM
        • Chiong E
        • Beltran H
        • Bristow RG
        • Williams SG
        Prostate cancer.
        Lancet. 2021; 398: 1075-1090
        • Sartor O
        • de Bono JS
        Metastatic prostate cancer.
        N Engl J Med. 2018; 378: 645-657
        • Westaby D
        • Fenor de La Maza MLD
        • Paschalis A
        • et al.
        A new old target: androgen receptor signaling and advanced prostate cancer.
        Annu Rev Pharmacol Toxicol. 2022; 62: 131-153
        • Mateo J
        • Seed G
        • Bertan C
        • et al.
        Genomics of lethal prostate cancer at diagnosis and castration resistance.
        J Clin Invest. 2020; 130: 1743-1751
        • Fraser M
        • Sabelnykova VY
        • Yamaguchi TN
        • et al.
        Genomic hallmarks of localized, non-indolent prostate cancer.
        Nature. 2017; 541: 359-364
        • Cooper CS
        • Eeles R
        • Wedge DC
        • et al.
        Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
        Nat Genet. 2015; 47: 367-372
        • Boutros PC
        • Fraser M
        • Harding NJ
        • et al.
        Spatial genomic heterogeneity within localized, multifocal prostate cancer.
        Nat Genet. 2015; 47: 736-745
        • Ladomery M
        Aberrant alternative splicing is another hallmark of cancer.
        Int J Cell Biol. 2013; 2013463786
        • Oltean S
        • Bates DO
        Hallmarks of alternative splicing in cancer.
        Oncogene. 2014; 33: 5311-5318
        • Rahman MA
        • Krainer AR
        • Abdel-Wahab O
        SnapShot: splicing alterations in cancer.
        Cell. 2020; 180: 208-2e1
        • Jimenez-Vacas JM
        • Herrero-Aguayo V
        • Montero-Hidalgo AJ
        • et al.
        Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer.
        EBioMedicine. 2020; 102547
        • Jimenez-Vacas JM
        • Herrero-Aguayo V
        • Gomez-Gomez E
        • et al.
        Spliceosome component SF3B1 as novel prognostic biomarker and therapeutic target for prostate cancer.
        Transl Res. 2019; 212: 89-103
        • Hormaechea-Agulla D
        • Jimenez-Vacas JM
        • Gomez-Gomez E
        • et al.
        The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.
        Faseb J. 2017; 31: 4682-4696
        • Hormaechea-Agulla D
        • Gahete MD
        • Jimenez-Vacas JM
        • et al.
        The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness.
        Mol Cancer. 2017; 16: 146
        • Fuentes-Fayos AC
        • Vazquez-Borrego MC
        • Jimenez-Vacas JM
        • et al.
        Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.
        Brain. 2020; 143: 3273-3293
        • Fuentes-Fayos AC
        • Perez-Gomez JM
        • GG ME
        • et al.
        SF3B1 inhibition disrupts malignancy and prolongs survival in glioblastoma patients through BCL2L1 splicing and mTOR/ss-catenin pathways imbalances.
        J Exp Clin Cancer Res. 2022; 41: 39
        • Paschalis A
        • Sharp A
        • Welti JC
        • et al.
        Alternative splicing in prostate cancer.
        Nat Rev Clin Oncol. 2018; 15: 663-675
        • Takayama KI
        Splicing factors have an essential role in prostate cancer progression and androgen receptor signaling.
        Biomolecules. 2019; 9: 131
        • Zeng Y
        • Wodzenski D
        • Gao D
        • et al.
        Stress-response protein RBM3 attenuates the stem-like properties of prostate cancer cells by interfering with CD44 variant splicing.
        Cancer Res. 2013; 73: 4123-4133
        • Zhao L
        • Li R
        • Shao C
        • Li P
        • Liu J
        • Wang K
        3p21.3 tumor suppressor gene RBM5 inhibits growth of human prostate cancer PC-3 cells through apoptosis.
        World J Surg Oncol. 2012; 10: 247
        • Yamamoto R
        • Osawa T
        • Sasaki Y
        • et al.
        Overexpression of p54(nrb)/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth.
        Oncotarget. 2018; 9: 10510-10524
        • Takayama KI
        • Suzuki T
        • Fujimura T
        • et al.
        Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF.
        Proc Natl Acad Sci U S A. 2017; 114: 10461-10466
        • Rasche N
        • Dybkov O
        • Schmitzova J
        • Akyildiz B
        • Fabrizio P
        • Luhrmann R
        Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre.
        EMBO J. 2012; 31: 1591-1604
        • Rasche N
        • Dybkov O
        • Schmitzová J
        • Akyildiz B
        • Fabrizio P
        • Lührmann R
        Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre.
        EMBO J. 2012; 31: 1591-1604
        • Van Nostrand EL
        • Freese P
        • Pratt GA
        • et al.
        A large-scale binding and functional map of human RNA-binding proteins.
        Nature. 2020; 583: 711-719
        • Xiao R
        • Chen JY
        • Liang Z
        • et al.
        Pervasive chromatin-RNA binding protein interactions enable RNA-based regulation of transcription.
        Cell. 2019; 178 (107–21.e18)
        • Soubise B
        • Jiang Y
        • Douet-Guilbert N
        • Troadec MB
        RBM22, a key player of Pre-mRNA splicing and gene expression regulation, is altered in Cancer.
        Cancers (Basel). 2022; 14: 643
        • Gao J
        • Aksoy BA
        • Dogrusoz U
        • et al.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci Signal. 2013; 6: l1
        • Cerami E
        • Gao J
        • Dogrusoz U
        • et al.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2: 401-404
        • Lapointe J
        • Li C
        • Higgins JP
        • et al.
        Gene expression profiling identifies clinically relevant subtypes of prostate cancer.
        Proc Natl Acad Sci U S A. 2004; 101: 811-816
        • Cancer Genome Atlas Research Network
        The molecular taxonomy of primary prostate Cancer.
        Cell. 2015; 163: 1011-1025
        • Abida W
        • Cyrta J
        • Heller G
        • Prandi D
        • Armenia J
        • Coleman I
        • et al.
        Genomic correlates of clinical outcome in advanced prostate cancer.
        Proc Natl Acad Sci U S A. 2019; 116: 11428-11436
        • Sáez-Martínez P
        • Jiménez-Vacas JM
        • León-González AJ
        • Herrero-Aguayo V
        • Montero Hidalgo AJ
        • Gómez-Gómez E
        • et al.
        Unleashing the diagnostic, prognostic and therapeutic potential of the neuronostatin/GPR107 system in prostate cancer.
        J Clin Med. 2020; 9: 1703
        • Jimenez-Vacas JM
        • Gomez-Gomez E
        • Montero-Hidalgo AJ
        • et al.
        Clinical utility of ghrelin-O-Acyltransferase (GOAT) enzyme as a diagnostic tool and potential therapeutic target in prostate cancer.
        J Clin Med. 2019; 8: 2056
        • Gómez-Gómez E
        • Jiménez-Vacas JM
        • Pedraza-Arévalo S
        • et al.
        Oncogenic role of secreted engrailed homeobox 2 (EN2) in prostate Cancer.
        J Clin Med. 2019; 8: 1400
        • Vandesompele J
        • De Preter K
        • Pattyn F
        • et al.
        Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.
        Genome Biol. 2002; 3 (RESEARCH0034)
        • Su ZZ
        • Lin J
        • Shen R
        • Fisher PE
        • Goldstein NI
        • Fisher PB
        Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family.
        Proc Nat Acad Sci of the U S A. 1996; 93: 7252-7257
        • Del Rio-Moreno M
        • Alors-Perez E
        • Borges de Souza P
        • et al.
        Peptides derived from the extracellular domain of the somatostatin receptor splicing variant SST5TMD4 increase malignancy in multiple cancer cell types.
        Transl Res. 2019; 211: 147-160
        • Frankish A
        • Diekhans M
        • Ferreira AM
        • et al.
        GENCODE reference annotation for the human and mouse genomes.
        Nucleic Acids Res. 2019; 47: D766-DD73
        • Patro R
        • Duggal G
        • Love MI
        • Irizarry RA
        • Kingsford C
        Salmon provides fast and bias-aware quantification of transcript expression.
        Nature methods. 2017; 14: 417-419
        • Soneson C
        • Love MI
        • Robinson MD
        Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences.
        F1000Res. 2015; 4: 1521
        • Ritchie ME
        • Phipson B
        • Wu D
        • et al.
        limma powers differential expression analyses for RNA-sequencing and microarray studies.
        Nucleic Acids Res. 2015; 43: e47
        • Trincado JL
        • Entizne JC
        • Hysenaj G
        • et al.
        SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions.
        Genome Biol. 2018; 19: 40
        • Alamancos GP
        • Pages A
        • Trincado JL
        • Bellora N
        • Eyras E
        Leveraging transcript quantification for fast computation of alternative splicing profiles.
        RNA. 2015; 21: 1521-1531
        • Gelman IH
        How the TRAMP model revolutionized the study of prostate Cancer progression.
        Cancer Res. 2016; 76: 6137-6139
        • Sarmento-Cabral A
        • F LL
        • Gahete MD
        • Castano JP
        • Luque RM
        Metformin reduces prostate Tumor growth, in a diet-dependent manner, by modulating multiple signaling pathways.
        Molecular cancer research: MCR. 2017; 15: 862-874
        • Munkley J
        • Li L
        • Krishnan SRG
        • et al.
        Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer.
        Elife. 2019; 8 (e47678)
        • Paschalis A
        • Welti J
        • Neeb AJ
        • et al.
        JMJD6 Is a Druggable oxygenase that regulates AR-V7 expression in prostate Cancer.
        Cancer Res. 2021; 81: 1087-1100
        • Horoszewicz JS
        • Leong SS
        • Kawinski E
        • et al.
        LNCaP model of human prostatic carcinoma.
        Cancer Res. 1983; 43: 1809-1818
        • Sramkoski RM
        • Pretlow 2nd, TG
        • Giaconia JM
        • et al.
        A new human prostate carcinoma cell line, 22Rv1.
        In Vitro Cell Dev Biol Anim. 1999; 35: 403-409
        • Sowalsky AG
        • Figueiredo I
        • Lis RT
        • et al.
        Assessment of Androgen receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer.
        Clin Cancer Res. 2022; 28: 3509-3525
        • Li Z
        • Guo Q
        • Zhang J
        • et al.
        The RNA-binding motif protein family in cancer: friend or foe?.
        Front Oncol. 2021; 11757135
        • Dvinge H
        • Kim E
        • Abdel-Wahab O
        • Bradley RK
        RNA splicing factors as oncoproteins and tumour suppressors.
        Nat Rev Cancer. 2016; 16: 413-430
        • De Maio A
        • Yalamanchili HK
        • Adamski CJ
        • et al.
        RBM17 interacts with U2SURP and CHERP to regulate expression and splicing of RNA-processing proteins.
        Cell Rep. 2018; 25 (726–36 e7)
        • Boultwood J
        • Pellagatti A
        • Cattan H
        • et al.
        Gene expression profiling of CD34+ cells in patients with the 5q- syndrome.
        Br J Haematol. 2007; 139: 578-589
        • Jimenez-Vacas JM
        • Herrero-Aguayo V
        • Montero-Hidalgo AJ
        • et al.
        Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer.
        EBioMedicine. 2020; 51102547
        • Verma S
        • Shankar E
        • Kalayci FNC
        • et al.
        Androgen Deprivation induces transcriptional reprogramming in prostate Cancer cells to develop stem cell-like characteristics.
        Int J Mol Sci. 2020; 21: 9568
        • Zhang L
        • Jiao M
        • Li L
        • et al.
        Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties.
        J Cancer Res Clin Oncol. 2012; 138: 675-686
        • Ge Y
        • Schuster MB
        • Pundhir S
        • et al.
        The splicing factor RBM25 controls MYC activity in acute myeloid leukemia.
        Nat Commun. 2019; 10: 172
        • Rose AE
        • Satagopan JM
        • Oddoux C
        • et al.
        Copy number and gene expression differences between African American and Caucasian American prostate cancer.
        J Transl Med. 2010; 8: 70
        • Powell IJ
        Epidemiology and pathophysiology of prostate cancer in African-American men.
        J Urol. 2007; 177: 444-449
        • Reddy S
        • Shapiro M
        • Morton Jr, R
        • Brawley OW
        Prostate cancer in black and white Americans.
        Cancer Metastasis Rev. 2003; 22: 83-86
        • Ka HI
        • Lee S
        • Han S
        • et al.
        Deubiquitinase USP47-stabilized splicing factor IK regulates the splicing of ATM pre-mRNA.
        Cell Death Discov. 2020; 6: 34
        • Das T
        • Park JK
        • Park J
        • et al.
        USP15 regulates dynamic protein-protein interactions of the spliceosome through deubiquitination of PRP31.
        Nucleic Acids Res. 2017; 45: 4866-4880
        • Song EJ
        • Werner SL
        • Neubauer J
        • et al.
        The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome.
        Genes Dev. 2010; 24: 1434-1447
        • Janowicz A
        • Michalak M
        • Krebs J
        Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7.
        Biochimica et biophysica acta. 2011; 1813: 1045-1049
        • Montaville P
        • Dai Y
        • Cheung CY
        • et al.
        Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22.
        Biochimica et biophysica acta. 2006; 1763: 1335-1343
        • Santamaria D
        • Barriere C
        • Cerqueira A
        • et al.
        Cdk1 is sufficient to drive the mammalian cell cycle.
        Nature. 2007; 448: 811-815
        • Gavet O
        • Pines J
        Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis.
        Dev Cell. 2010; 18: 533-543
        • Boddy JL
        • Fox SB
        • Han C
        • et al.
        The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer.
        Clin Cancer Res. 2005; 11: 7658-7663
        • Keith B
        • Johnson RS
        • Simon MC
        HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression.
        Nat Rev Cancer. 2011; 12: 9-22
        • Cimprich KA
        • Cortez D
        ATR: an essential regulator of genome integrity.
        Nat Rev Mol Cell Biol. 2008; 9: 616-627
        • Johnson N
        • Cai D
        • Kennedy RD
        • et al.
        Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.
        Mol Cell. 2009; 35: 327-339
        • Johnson N
        • Li YC
        • Walton ZE
        • et al.
        Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.
        Nat Med. 2011; 17: 875-882
        • Yazinski SA
        • Comaills V
        • Buisson R
        • et al.
        ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
        Genes Dev. 2017; 31: 318-332
        • Kim H
        • Xu H
        • George E
        • et al.
        Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.
        Nat Commun. 2020; 11: 3726
        • Neeb A
        • Herranz N
        • Arce-Gallego S
        • et al.
        Advanced prostate cancer with ATM loss: PARP and ATR inhibitors.
        Eur Urol. 2021; 79: 200-211
        • Murai J
        • Huang SY
        • Das BB
        • et al.
        Trapping of PARP1 and PARP2 by clinical PARP inhibitors.
        Cancer Res. 2012; 72: 5588-5599
        • de Bono J
        • Mateo J
        • Fizazi K
        • et al.
        Olaparib for metastatic castration-resistant prostate cancer.
        N Engl J Med. 2020; 382: 2091-2102