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. 2021 Jan 22:14:637-651.
doi: 10.2147/OTT.S287464. eCollection 2021.

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Bolin Chen  1 , Chengcheng Dong  2 , Fang Wang  2 , Jiacai Wu  2   3
Affiliations

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Bolin Chen et al. Onco Targets Ther. .

Abstract

Background: Novel inhibitor of histone acetyltransferase repressor (NIR), a corepressor with a novel inhibitor of histone acetyltransferase (INHAT) activity, has been reported to be a negative modulator of p53 and a regulator of the cell cycle in cancer cells. However, the role of NIR in the progression of breast cancer remains elusive.

Materials and methods: Oncomine database was used to analyze the mRNA levels and prognosis value of NIR in breast cancer. We performed loss-of-function and gain-of-function studies using lentivirus expressing shRNA targeting NIR, enhancer of zeste homolog 2 (EZH2) and forkhead box O3 (FOXO3) or lentivirus expressing NIR or FOXO3, respectively. Cell proliferation and colony formation assays were performed. Co-immunoprecipitation (Co-IP) and immunoprecipitation (IP) were performed to identify the interaction between NIR and polycomb repressive complex 2 (PRC2) subunits. ChIP assay was used to identify the enrichment of NIR, EZH2, H3K27ac and H3K27me3 at the FOXO3 promoter region and the regulation of H3K27 modification at the FOXO3 promoter by NIR.

Results: High levels of NIR expression were correlated with poor prognosis in breast cancer patients. Knockdown of NIR suppressed the proliferation of breast cancer cells. Mechanically, NIR was recruited by EZH2 to the promoter vicinity of FOXO3 via direct protein-protein interaction. Silencing NIR increased H3K27ac and decreased H3K27me3 levels at the FOXO3 promoter, resulting in enhancing FOXO3 expression. In accordance with this, growth inhibition of breast cancer cells caused by silencing of NIR could be reversed by FOXO3 knockdown.

Conclusion: NIR knockdown inhibited proliferation by switching the H3K27me3 and H3K27ac marks at the FOXO3 promoter to promote FOXO3 transcription, and this effect depends on the physical interaction between NIR and PRC2 in breast cancer cells. Our results suggest that NIR might be a potential target for breast cancer treatment.

Keywords: Breast cancer; EZH2; FOXO3; NIR; PRC2.

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Conflict of interest statement

The authors proclaim no conflict of interests.

Figures

Figure 1
Figure 1
High level of NIR expression is associated with poor survival in breast cancer patients.
Figure 2
Figure 2
Knockdown of NIR (novel INHAT repressor) represses cell proliferation and colony formation in breast cancer cells.
Figure 3
Figure 3
Re-expression NIR rescues the cell proliferation in NIR-silenced MDA-MB231 cells.
Figure 4
Figure 4
NIR directly associates with the PRC2 complex via EZH2.
Figure 5
Figure 5
EZH2 and NIR co-regulate FOXO3 expression in breast cancer cells.
Figure 6
Figure 6
NIR, EZH2, H3K27me3, and H3K27ac are occupied at genomic loci of FOXO3.
Figure 7
Figure 7
EZH2 recruits NIR to the vicinity promoter of FOXO3.
Figure 8
Figure 8
NIR modulates the modification of H3K27 at the FOXO3 promoter region.
Figure 9
Figure 9
NIR regulates breast cancer cell proliferation via FOXO3.
See this image and copyright information in PMC

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References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492 - DOI - PubMed
    1. Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389(10074):1134–1150. doi:10.1016/S0140-6736(16)31891-8 - DOI - PubMed
    1. Lee EY, Muller WJ. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol. 2010;2(10):a003236. doi:10.1101/cshperspect.a003236 - DOI - PMC - PubMed
    1. Hublitz P, Kunowska N, Mayer UP, et al. NIR is a novel INHAT repressor that modulates the transcriptional activity of p53. Genes Dev. 2005;19(23):2912–2924. doi:10.1101/gad.351205 - DOI - PMC - PubMed
    1. Duteil D, Tourrette Y, Eberlin A, et al. The histone acetyltransferase inhibitor Nir regulates epidermis development. Development. 2018;145(6):dev158543. doi:10.1242/dev.158543 - DOI - PubMed