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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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Research Article Cell biology Oncology Article has an altmetric score of 3

Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

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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 2

FoxO3 regulates Dicer expression and miRNA biosynthesis.

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FoxO3 regulates Dicer expression and miRNA biosynthesis.
(A) LM2 cells w...
(A) LM2 cells were infected with lentivirus encoding FoxO3 shRNAs. Cell lysates and RNA were extracted and subjected to Western blotting (upper panel) or qRT-PCR (lower panel), respectively. Results are shown as mean ± SD. n = 3 independent experiments. (B) Luciferase assay of HEK-293T cells cotransfected with the Dicer promoter luciferase reporter and the indicated FoxO3 constructs. Upper panel: schematic of the Dicer promoter, showing the sequence of the putative FBEs in the human Dicer promoter region and the substitution mutations introduced into this FBE sequence. Lower panel: luciferase reporter activity results are depicted as bar graph with mean ± SD. n = 3 independent experiments. ‡P < 0.001; **P < 0.01, 2-way ANOVA with Bonferroni’s post hoc test. (C) ChIP assay in LM2 cells. Diagram of the Dicer promoter region with the amplicons used for PCR analysis (upper panel). ChIP analysis for the presence of FoxO3 at the Dicer promoter in LM2 cells with or without FoxO3 depletion (lower panel). (D) Data from C are depicted as bar graph with mean ± SD. n = 3 independent experiments. ‡P < 0.001, 2-way ANOVA with Bonferroni’s post hoc test. Con, control. (E) Dots show the ratio of miRNA expression levels in MDA–MB-231 cells depleted of FoxO3. (F and G) LM2 cells were infected with lentivirus encoding the indicated shRNAs. RNA was extracted and subjected to qRT-PCR. Results are shown as mean ± SD. n = 3 independent experiments. (H) LM2 cells stably expressing FLAG-Dicer and the indicated shRNAs were subjected to Western blotting.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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