Study reveals the role of epigenetics in prostate cancer radioresistance

send to a friend share this

Study reveals the role of epigenetics in prostate cancer radioresistance

Tuesday, 21.11.2023

Researchers from the Cancer Biology & Epigenetics Group at the Research Center of IPO Porto, Portugal have revealed a pivotal link between epigenetic regulation and prostate cancer radioresistance. The study, entitled "Epigenetic Regulation of TP53 is Involved in Prostate Cancer Radioresistance and DNA Damage Response Signaling," was recently published in the prestigious journal Signal Transduction and Targeted Therapy. Prostate cancer remains a significant health concern, with the radioresistance phenomenon posing a significant obstacle to effective treatment, which might ultimately result in long-term recurrence or disease progression. The published study offers novel insights into the underlying mechanisms driving radiotherapy resistance and provides hope of finding new complementary therapeutic strategies. The research primarily focuses on p53, often referred to as the “guardian of the genome”, as it plays critical functions in DNA damage response signalling. Notably, the team found that epigenetic modifications in prostate cancer radioresistant cells play a central role in reshaping TP53 expression. This work is of utmost importance for the field, and it paves the way for further studies and potential clinical applications aiming at overcoming prostate cancer radioresistance. The full article version can be accessed in the latest journal issue (DOI: 10.1038/s41392-023-01639-6) 


Catarina Macedo-Silva1,2; Vera Miranda-Gonçalves1,3; Nuno Tiago Tavares1; Daniela Barros-Silva1; Joana Lencart4,5; João Lobo1,3,6; Ângelo Oliveira7; Margareta P. Correia1,3; Lucia Altucci2,8,9#; Carmen Jerónimo1,3#* # Joint senior authors

(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.


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, 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.

Signal Transduction and Targeted Therapy

https://www.nature.com/articles/s41392-023-01639-6