A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

被引:8
作者
Mourkioti, Ioanna [1 ]
Polyzou, Aikaterini [1 ]
Veroutis, Dimitris [1 ]
Theocharous, George [1 ]
Lagopati, Nefeli [1 ,2 ,3 ]
Gentile, Emanuela [4 ]
Stravokefalou, Vasiliki [5 ]
Thanos, Dimitris-Foivos [1 ]
Havaki, Sophia [1 ]
Kletsas, Dimitris [6 ]
Panaretakis, Theocharis [4 ]
Logothetis, Christopher J. [4 ]
Stellas, Dimitris [5 ]
Petty, Russell [7 ]
Blandino, Giovanni [8 ]
Papaspyropoulos, Angelos [1 ,2 ]
Gorgoulis, Vassilis G. [1 ,2 ,7 ,9 ,10 ,11 ]
机构
[1] Natl & Kapodistrian Univ Athens, Med Sch, Dept Histol & Embryol, Mol Carcinogenesis Grp, Athens, Greece
[2] Biomed Res Fdn, Acad Athens, Athens, Greece
[3] Natl & Kapodistrian Univ Athens, Med Sch, Dept Basic Med Sci, Lab Biol, Athens, Greece
[4] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
[5] Natl Hellen Res Fdn, Inst Chem Biol, Athens 11635, Greece
[6] Natl Ctr Sci Res Demokritos, Inst Biosci & Applicat, Lab Cell Proliferat & Ageing, Aghia Paraskevi, Greece
[7] Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland
[8] IRCCS Regina Elena Natl Canc Inst, Dept Res, Oncogen & Epigenet Unit, Diag & Innovat Technol, Rome, Italy
[9] Univ Manchester, Fac Inst Canc Sci, Manchester Acad Hlth Sci Ctr, Manchester, England
[10] Natl & Kapodistrian Univ Athens, Ctr New Biotechnol & Precis Med, Med Sch, Athens, Greece
[11] Univ Surrey, Fac Hlth & Med Sci, Guildford, England
关键词
Prostate cancer; AR signaling blockade; Enzalutamide; GATA2-CDC6; axis; Cellular senescence; ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE RESPONSE; RNA-SEQ DATA; CELLULAR SENESCENCE; GLUCOCORTICOID-RECEPTOR; ENZALUTAMIDE RESISTANCE; TUMOR-SUPPRESSOR; CELLS; EXPRESSION; MECHANISMS;
D O I
10.1186/s13046-023-02769-z
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundProstate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed.MethodsAndrogen-dependent (LNCaP) and -independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy.ResultsWe demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression.ConclusionsWe identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.
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页数:20
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共 81 条
  • [11] Androgen-deprivation induced senescence in prostate cancer cells is permissive for the development of castration-resistance but susceptible to senolytic therapy
    Carpenter, Valerie
    Saleh, Tareq
    Lee, So Min
    Murray, Graeme
    Reed, Jason
    Souers, Andrew
    Faber, Anthony C.
    Harada, Hisashi
    Gewirtz, David A.
    [J]. BIOCHEMICAL PHARMACOLOGY, 2021, 193
  • [12] The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer
    Chaytor, Lewis
    Simcock, Matthew
    Nakjang, Sirintra
    Heath, Richard
    Walker, Laura
    Robson, Craig
    Jones, Dominic
    Gaughan, Luke
    [J]. MOLECULAR CANCER RESEARCH, 2019, 17 (06) : 1264 - 1278
  • [13] DEWINTER JAR, 1994, AM J PATHOL, V144, P735
  • [14] Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
    Di Micco, Raffaella
    Fumagalli, Marzia
    Cicalese, Angelo
    Piccinin, Sara
    Gasparini, Patrizia
    Luise, Chiara
    Schurra, Catherine
    Garre, Massimiliano
    Nuciforo, Paolo Giovanni
    Bensimon, Aaron
    Maestro, Roberta
    Pelicci, Pier Giuseppe
    di Fagagna, Fabrizio d'Adda
    [J]. NATURE, 2006, 444 (7119) : 638 - 642
  • [15] STAR: ultrafast universal RNA-seq aligner
    Dobin, Alexander
    Davis, Carrie A.
    Schlesinger, Felix
    Drenkow, Jorg
    Zaleski, Chris
    Jha, Sonali
    Batut, Philippe
    Chaisson, Mark
    Gingeras, Thomas R.
    [J]. BIOINFORMATICS, 2013, 29 (01) : 15 - 21
  • [16] Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis
    Evangelou, Konstantinos
    Veroutis, Dimitris
    Paschalaki, Koralia
    Foukas, Periklis G.
    Lagopati, Nefeli
    Dimitriou, Marios
    Papaspyropoulos, Angelos
    Konda, Bindu
    Hazapis, Orsalia
    Polyzou, Aikaterini
    Havaki, Sophia
    Kotsinas, Athanassios
    Kittas, Christos
    Tzioufas, Athanasios G.
    De Leval, Laurence
    Vassilakos, Demetris
    Tsiodras, Sotirios
    Stripp, Barry R.
    Papantonis, Argyris
    Blandino, Giovanni
    Karakasiliotis, Ioannis
    Barnes, Peter J.
    Gorgoulis, Vassilis G.
    [J]. EUROPEAN RESPIRATORY JOURNAL, 2022, 60 (02)
  • [17] Androgen deprivation induces senescence characteristics in prostate cancer cells in vitro and in vivo
    Ewald, Jonathan A.
    Desotelle, Joshua A.
    Church, Dawn R.
    Yang, Bing
    Huang, Wei
    Laurila, Timo A.
    Jarrard, David F.
    [J]. PROSTATE, 2013, 73 (04) : 337 - 345
  • [18] Targeting DNMTs to Overcome Enzalutamide Resistance in Prostate Cancer
    Farah, Elia
    Zhang, Zhuangzhuang
    Utturkar, Sagar M.
    Liu, Jinpeng
    Ratliff, Timothy L.
    Liu, Xiaoqi
    [J]. MOLECULAR CANCER THERAPEUTICS, 2022, 21 (01) : 193 - 205
  • [19] MYC-Mediated Ribosomal Gene Expression Sensitizes Enzalutamide-resistant Prostate Cancer Cells to EP300/CREBBP Inhibitors
    Furlan, Tobias
    Kirchmair, Alexander
    Sampson, Natalie
    Puhr, Martin
    Gruber, Martina
    Trajanoski, Zlatko
    Santer, Frederic R.
    Parson, Walther
    Handle, Florian
    Culig, Zoran
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2021, 191 (06) : 1094 - 1107
  • [20] Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
    Galanos, Panagiotis
    Vougas, Konstantinos
    Walter, David
    Polyzos, Alexander
    Maya-Mendoza, Apolinar
    Haagensen, Emma J.
    Kokkalis, Antonis
    Roumelioti, Fani-Marlen
    Gagos, Sarantis
    Tzetis, Maria
    Canovas, Begona
    Igea, Ana
    Ahuja, Akshay K.
    Zellweger, Ralph
    Havaki, Sofia
    Kanavakis, Emanuel
    Kletsas, Dimitris
    Roninson, Igor B.
    Garbis, Spiros D.
    Lopes, Massimo
    Nebreda, Angel
    Thanos, Dimitris
    Blow, J. Julian
    Townsend, Paul
    Sorensen, Claus Storgaard
    Bartek, Jiri
    Gorgoulis, Vassilis G.
    [J]. NATURE CELL BIOLOGY, 2016, 18 (07) : 777 - +