Identification of Estrogen Receptor-Related Receptor Gamma as a Direct Transcriptional Target of Angiogenin

Nuclear translocation of angiogenin (ANG) is essential for the proliferation of its target cells. ANG promotes rRNA synthesis, while whether it regulates mRNA transcription remains unknown. Using the chromatin immunoprecipitation method, we have identified 12 ANG-binding sequences. One of these sequences lies in the estrogen receptor-related receptor gamma (ERR gamma) gene which we designated as ANG-Binding Sequence within ERR gamma (ABSE). ABSE exhibited ANG-dependent repressor activity in the luciferase reporter system. Down-regulation of ANG increased ERR gamma expression, and active gene marker level at the ABSE region. The expression levels of ERR gamma targets genes, p21(WAF/CIP) and p27(KIP1), and the occupation of ERR gamma on their promoter regions were increased in ANG-deficient cells accordingly. Furthermore, knockdown of ERR gamma promoted the proliferation rate in ANG-deficient breast cancer cells. Finally, immunohistochemistry staining showed negative correlation between ANG and ERR gamma in breast cancer tissue. Altogether, our study provides evidence that nuclear ANG directly binds to the ABSE of ERR gamma gene and inhibits ERR gamma transcription to promote breast cancer cell proliferation.