Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis

Líu, Hao; Song, Ying; Qiu, Huishi; Liu, Yanzhen; Luo, Kai; Yi, Yanmei; Jiang, Guanmin; Lu, Mengji; Zhang, Zhijie; Yin, Jun; Zeng, Shanshan; Chen, Xiangzhou; Deng, Min; Jia, Xiaoting; Gu, Yue; Chen, Danyang; Zheng, Guopei; He, Zhiwei

doi:10.1038/s41418-019-0389-3

Cited by 119 publications

(81 citation statements)

References 62 publications

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“…We previously observed a negative correlation between FOXO3a expression and lymph node metastasis in breast cancer tissues (Supplementary Table 1 ) [ 25 ]. To determine the association between FOXO3a and tumor metastatic ability, we analyzed the protein expression of FOXO3a in several breast cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites [ 32 ]. Several lines of evidence demonstrated that downregulation of FOXO3a affects phenotypes such as cell proliferation, EMT, and stemness that contribute to breast cancer progression and poor response to therapies [ 10 , 25 , 33 , 34 ]. In the current study, our findings demonstrated that FOXO3a expression is inversely correlated with the migration ability of breast cancer cells and overexpression of FOXO3a suppresses breast cancer invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

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FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis

et al. 2020

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Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis

et al. 2020

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“…Separately, FOXO3a is known to suppress breast cancer stem cells (BCSC) properties and tumorigenicity via inhibition of oncogenic FOXMI/SOX2 signaling. In this context, DNA methyl transferase (DNMT1)-mediated FOXO3a promoter hypermethylation leads to downregulation of FOXO3a expression in BCa, leading to the maintenance of BCSC population and associated with development of drug resistance [ 136 ]. Further, FOXO3a in collaboration with another TSG liver kinase B1 (LKB1) regulate CD44 expression and play a central role in CSC maintenance in pancreatic ductal adenocarcinoma [ 137 ]…”

Section: Foxo Familymentioning

confidence: 99%

Tumor Suppressors Having Oncogenic Functions: The Double Agents

Datta

Chakraborty

Basu³

et al. 2020

Cells

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Cancer progression involves multiple genetic and epigenetic events, which involve gain-of-functions of oncogenes and loss-of-functions of tumor suppressor genes. Classical tumor suppressor genes are recessive in nature, anti-proliferative, and frequently found inactivated or mutated in cancers. However, extensive research over the last few years have elucidated that certain tumor suppressor genes do not conform to these standard definitions and might act as “double agents”, playing contrasting roles in vivo in cells, where either due to haploinsufficiency, epigenetic hypermethylation, or due to involvement with multiple genetic and oncogenic events, they play an enhanced proliferative role and facilitate the pathogenesis of cancer. This review discusses and highlights some of these exceptions; the genetic events, cellular contexts, and mechanisms by which four important tumor suppressors—pRb, PTEN, FOXO, and PML display their oncogenic potentials and pro-survival traits in cancer.

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“…Since our data showed that depletion of NIR enhanced FOXO3 expression while suppressing cell proliferation in MDA-MB231 cells, and FOXO3 has been shown to regulate cell growth. 19 We investigated whether NIR regulated cell proliferation via FOXO3 in breast cancer cells. Indeed, we observed that the enhanced proliferation of MDA-MB231 cells caused by overexpression of NIR can be reversed by ectopic FOXO3 expression ( Figure 9A and B ).…”

Section: Resultsmentioning

confidence: 99%

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Chen¹,

Dong²,

Wang³

et al. 2021

OTT

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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. Coimmunoprecipitation (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.

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Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis

Cited by 119 publications

References 62 publications

FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis

FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis

Tumor Suppressors Having Oncogenic Functions: The Double Agents

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

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