Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish
Pages (from-to)2159-2175
Number of pages17
JournalJournal of Clinical Investigation
Issue number6
StatePublished - 1 Jun 2017


Dive into the research topics of 'Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis'. Together they form a unique fingerprint.

Cite this