Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis
Lei Zhang, … , Y. Eugene Chin, Han You
Lei Zhang, … , Y. Eugene Chin, Han You
Published April 24, 2017
Citation Information: J Clin Invest. 2017;127(6):2159-2175. https://doi.org/10.1172/JCI90077.
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Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

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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Figure 5

FoxO3 regulates metastasis through Dicer.

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FoxO3 regulates metastasis through Dicer. (A–D) MCF-7 cells (A and ...
(A–D) MCF-7 cells (A and B) or LM2 cells (C and D) infected with the indicated lentiviral constructs were subjected to Transwell migration and invasion assays. Results are shown as mean ± SD. n = 3 independent experiments. Scale bars: 50 μm. ‡P < 0.001; **P < 0.01; *P < 0.05, 2-way ANOVA with Bonferroni’s post hoc test. (E) Experimental design for in vivo metastasis analysis using orthotropic injection. (F–I) Luciferase-labeled MCF-7 cells (F and G) or LM2 cells (H and I) infected with lentivirus encoding the indicated shRNAs were injected into the mammary fat pads of nude mice. Representative bioluminescence imaging (BLI) images of mice with spontaneous lung metastasis (F and H) and quantification of the bioluminescence signal (G and I) are shown. Results represent mean ± SD; n = 8 mice per group. ‡P < 0.001; **P < 0.01; *P < 0.05, 2-way ANOVA with Bonferroni’s post hoc test. (J) MCF-7 cells were infected with lentivirus encoding FoxO3 and/or Dicer shRNAs. Cell lysates were extracted and subjected to Western blotting. (K) Cells from J were subjected to Transwell migration and invasion assays. Results are shown as mean ± SD. n = 3 independent experiments.