p53/HMGB1 Complexes Regulate Autophagy and Apoptosis.

Cancer Research

PubMedID: 22345153

Livesey KM, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC, Zhang L, Manfredi JJ, Zeh HJ, Li L, Lotze MT, Tang D. p53/HMGB1 Complexes Regulate Autophagy and Apoptosis. Cancer Res. 2012;72(8):1996-2005.
The balance between apoptosis and autophagy is important in tumor development and response to therapy. In this study, we show that the chromatin-binding protein high mobility group box 1 (HMGB1) forms a complex with p53 to regulate the balance between tumor cell death and survival. Loss of p53 increased the expression of cytosolic HMGB1 and induced autophagy in colon cancer cells. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increased p53 cytosolic localization and decreased autophagy. p53 therefore acts as a negative regulator of the HMGB1/Beclin 1 complex, as HMGB1 promoted autophagy in the setting of diminished p53. In addition, HMGB1-mediated autophagy promoted tumor cell survival in the setting of p53-dependent processes. We also found that colorectal cancer patients show a progressive increase in p53 expression and enhanced cytosolic HMGB1 with advancing stage. The HMGB1/p53 complex influenced the cytoplasmic localization of the reciprocal binding partner, thereby regulating subsequent levels of autophagy and apoptosis. Together, these insights provide a novel link between HMGB1 and p53 in the crossregulation of apoptosis and autophagy in the setting of cell stress, providing insights into their reciprocal roles in carcinogenesis.