Prostate cancer (PCa) is the most commonly diagnosed cancer among males and is the second leading cause of cancer-related male death worldwide. TMPRSS2-ERG (T2E) gene fusion is the most common gene rearrangement in PCa patients, and it account for nearly 50% of PCa patients in the western world; In Asia patients, it also account for about 25%. The result of T2E gene fusion is the aberrant increasing expression of ERG oncoprotein. As a transcription factor, ERG oncoprotein can further activate a series of downstream targets, most of which are oncogenes, thus leading the initiation, deterioration and invasion of PCa. Hence, it is utmost important to develop novel ways to target ERG oncoprotein.
On September 17, the international journal, Molecular Cell (IF=15.584) , published a research article from Tongji Hospital Affiliated to Tongji University titled: DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3β and WEE1. Dr. HONG Zhe is the first author. Prof. Huang Haojie, Prof. WU Denglong and Dr. WU Qiang are the correspondence authors.
This research, for the first time, found that DNA damage therapy (Radiation and Chemotherapy) could target ERG oncoprotein and lead its degradation, which is related to the PTEN function. With an intact PTEN function, PTEN downstream kinase GSK3β could be activated, together with the WEE1 kinase, which is activating by the DNA damage, phosphorylate ERG oncoprotein and mediate ERG degradation. This research further uncovered that in the patient with PTEN deletion, combination of AKT kinase inhibitor and DNA damage agent could reverse the resistance of ERG degradation, and resensitize the sensitivity of PCa to DNA damage treatments. At the same time, the study pointed out that the failure of ERG degradation is one of the most crucial reasons that cause PCa resistance to radiation therapy.
This study focuses on TMPRSS2-ERG gene fusion PCa patients, which is the largest population of PCa patients. Profoundly reveals the relation between PTEN function and ERG oncoprotein destruction, which aims to provide precision therapy for PCa treatments.
The original link：https://pubmed.ncbi.nlm.nih.gov/32871104/