Abstract
Geminin expression is essential for embryonic development and the maintenance of
chromosomal integrity. In spite of this protective role, geminin is also
frequently overexpressed in human cancers and the molecular mechanisms
underlying its role in tumor progression remain unclear. The histone deacetylase
HDAC3 modulates transcription factors to activate or suppress transcription.
Little is known about how HDAC3 specifies substrates for modulation among highly
homologous transcription factor family members. Here, we have demonstrated that
geminin selectively couples the transcription factor forkhead box O3 (FoxO3) to
HDAC3, thereby specifically facilitating FoxO3 deacetylation. We determined that
geminin–associated HDAC3 deacetylates FoxO3 to block its transcriptional
activity, leading to downregulation of the downstream FoxO3 target Dicer, an
RNase that suppresses metastasis. Breast cancer cells depleted of geminin or
HDAC3 exhibited poor metastatic potential that was attributed to reduced
suppression of the FoxO3-Dicer axis. Moreover, elevated levels of geminin,
HDAC3, or both together with decreased FoxO3 acetylation and reduced Dicer
expression were detected in aggressive human breast cancer specimens. These
results underscore a prominent role for geminin in promoting breast cancer
metastasis via the enzyme-substrate–coupling mechanism in HDAC3-FoxO3 complex
formation.
Authors
Lei Zhang, Meizhen Cai, Zhicheng Gong, Bingchang Zhang, Yuanpei Li, Li Guan, Xiaonan Hou, Qing Li, Gang Liu, Zengfu Xue, Muh-hua Yang, Jing Ye, Y. Eugene Chin, Han You
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