Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling  

作　　者：Catarina Macedo-Silva Vera Miranda-Gonçalves Nuno Tiago Tavares Daniela Barros-Silva Joana Lencart João Lobo Ângelo Oliveira Margareta PCorreia Lucia Altucci Carmen Jerónimo 

机构地区：[1]Cancer Biology&Epigenetics Group,Research Center of IPO Porto(CI-IPOP)/CI-IPOP@RISE(Health Research Network),Portuguese Oncology Institute of Porto(IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca(Porto.CCC),R.Dr.António Bernardino de Almeida,4200-072,Porto,Portugal [2]Department of Precision Medicine,University of Campania“Luigi Vanvitelli”,80138,Naples,Italy [3]Department of Pathology and Molecular Immunology,ICBAS-School of Medicine&Biomedical Sciences,University of Porto,R.Jorge de Viterbo Ferreira 228,4050-313,Porto,Portugal [4]Medical Physics,Radiobiology and Radiation Protection Group-Research Center of IPO Porto(CI-IPOP)/CI-IPOP@RISE(Health Research Network),Portuguese Oncology Institute of Porto(IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca(Porto.CCC),R.Dr.António Bernardino de Almeida,4200-072,Porto,Portugal [5]Department of Medical Physics,Portuguese Oncology Institute of Porto,4200-072,Porto,Portugal [6]Department of Pathology,Portuguese Oncology Institute of Porto,Porto,Portugal [7]Department of Radiation Oncology,Portuguese Oncology Institute of Porto,Porto,Portugal [8]BIOGEM,Molecular Biology and Genetics Research Institute,83100,Avellino,Italy [9]IEOS,Institute of Endocrinology and Oncology,80100,Naples,Italy

出　　处：《Signal Transduction and Targeted Therapy》2023年第11期5404-5416,共13页信号转导与靶向治疗（英文）

摘　　要：External beam radiotherapy(RT)is a leading first-line therapy for prostate cancer(PCa),and,in recent years,significant advances have been accomplished.However,RT resistance can arise and result in long-term recurrence or disease progression in the worst-case scenario.Thus,making crucial the discovery of new targets for PCa radiosensitization.Herein,we generated a radioresistant PCa cell line,and found p53 to be highly expressed in radioresistant PCa cells,as well as in PCa patients with recurrent/disease progression submitted to RT.Mechanism dissection revealed that RT could promote p53 expression via epigenetic modulation.Specifically,a decrease of H3K27me3 occupancy at TP53 gene promoter,due to increased KDM6B activity,was observed in radioresistant PCa cells.Furthermore,p53 is essential for efficient DNA damage signaling response and cell recovery upon stress induction by prolonged fractionated irradiation.Remarkably,KDM6B inhibition by GSK-J4 significantly decreased p53 expression,consequently attenuating the radioresistant phenotype of PCa cells and hampering in vivo 3D tumor formation.Overall,this work contributes to improve the understanding of p53 as a mediator of signaling transduction in DNA damage repair,as well as the impact of epigenetic targeting for PCa radiosensitization.

关 键 词：TP53 DAMAGE cancer 

分 类 号：R737.25[医药卫生—肿瘤]