期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 44, 页码 16090-16095出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0505585102
关键词
histone deacetylase inhibitors; tumor selectivity; oncogene
Inhibitors of histone deacetylases (HDACls) are a new generation of anticancer agents that selectively kill tumor cells. However, the molecular basis for their tumor selectivity is not well understood. We investigated the effects of HDACls on the oncogenic Rb-E2F1 pathway, which is frequently deregulated in human cancers. Here, we report that cancer cells with elevated E2F1 activity, caused either by enforced E2F1 expression, or by E1A oncogene expression, are highly susceptible to HDACl-induced cell death. This E2F1-mediated apoptosis is neither p53- nor p73-dependent but proceeds through selective induction of proapoptotic BH3-only protein Bim. We show that Bim is a direct target of E2F1 and that HDAC inhibition promotes the recruitment of E2F1 to the Bim promoter. Moreover, silencing of Bim by specific small interfering RNA (siRNA) effectively abolishes the E2F1-mediated cell death sensitization to HDACls. These findings suggest that the oncogenic E2F1 pathway participates in HDACls-induced apoptosis in cancer cells and underscore the importance of Bim as a key mediator of oncogene-induced apoptosis. Our study provides an important insight into the molecular mechanism of tumor selectivity of HDACls and predicts that, clinically, HDACls will be more effective in tumors with high E2F1 activity.
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