DDB2降解雄性激素受體蛋白之探討

Abstract

DDB2 is a well-known WD40 protein that associates with DDB1 and involved in DDB1-Cul4 E3 complex. DDB1-DDB2 heterodimer was in nucleotide excision repair (NER) pathway which UV induced DNA damage repairs. AR, a well-studied molecule, is known to be highly expressed in prostate cancer and functions as an important transcription factor to regulate the expression of a great number of genes, then guides the prostate cancer cell into a malignant stage or maintains prostate cancer cell growth. We previously showed that DDB2 is a novel AR binding protein. Knockdown endogenous DDB1, CUL4A resulted in increased AR protein amount, implying that DDB2 may degrade AR protein via DDB1-CUL4 E3 ligase pathway. Here, we presented the DNA-damage inducing DDB2 that decreasing AR protein. After we introduced DDB2 in LNCaP cell results in the decreased AR protein. Moreover, knowckdown DDB2 expression in LNCaP cells increases AR protein. To demonstrate the mechanism of DDB2 destabilizing AR, we found that DDB2-N terminal domain can interact with AR, but only full length DDB2 has function to degrade AR. We also mapped that AR HBD domain is responsible for DDB2 binding.