Mechanistic Study of Proapoptotic Daxx-Par4 Axis in Prostate Cancer

摘要

Compelling evidence suggests that autophagy acts as a tumor suppressor mechanism. However, the molecular mechanisms for tumorigenesis inhibition via autophagy remain elusive. Two key players in autophagy have begun to emerge: DAPK1 and DAXX. DAPK1 is a tumor suppressor, and its expression is lost in many cancers. DAPK1 is potently repressed via epigenetic mechanisms by the transcriptional repressor DAXX in conjunction with transcription factor RELB. DAXX has potent growth-enhancing effects on primary malignancies, however, the mechanism by which DAXX promotes tumorigenicity remains enigmatic. Using a mouse subcutaneous xenograft model, an increase in autophagy markers, including DAPK1 (an inducer of autophagy), was observed in DAXX K/D subcutaneous tumors, suggesting that DAXX represses the autophagy program. Furthermore, by using a linear regression analysis, an inverse correlation was found between DAXX and DAPK1 mRNA expression in a diverse collection of human tumor cell lines and tumor specimens, suggesting that DAXX's role as a transcriptional repressor of the DAPK1 gene is broadly relevant to tumor biology. These observations suggest that DAXX has an inhibitory effect on autophagy in vivo. DAXX may promote prostate tumorigenesis by inhibiting autophagy.