A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis.

The oncoprotein c-Myc is a key transcription factor with essential functions in the nucleolus (NO) to regulate ribosomal RNA (rRNA) synthesis, ribosome biogenesis, and cell proliferation. Yet, the mechanism that regulates the distribution and function of nucleolar c-Myc is still not completely understood. In this study, we identified nucleolar protein ENBA1 binding protein 2 (EBP2) as a novel functional binding partner of c-Myc. We found that coexpression of EBP2 markedly relocalized c-Myc from the nucleus to the NO, whereas depletion of EBP2 reduced the nucleolar distribution of c-Myc. Further study indicated that EBP2 is a direct binding partner of c-Myc and can block the degradation of c-Myc in a FBW7 (F-box and WD repeat domain containing 7)-independent manner. Moreover, EBP2 is a transcriptional target of c-Myc. c-Myc can bind to the promoter of EBP2 and positively regulate the EBP2 expression. Both protein and mRNA levels of EBP2 are upregulated in lung cancer samples and positively correlated with c-Myc expression. Functionally, EBP2 promotes c-Myc-mediated rRNA synthesis and cell proliferation. Collectively, our study indicates that EBP2 is a novel binding partner of c-Myc that regulates the function of nucleolar c-Myc, cell proliferation, and tumorigenesis via a positive feedback loop.