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Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

ABSTRACT: Cancer stem cells (CSCs) are regarded as the main cell type responsible for the initiation, metastasis, drug resistance, and recurrence of cancer. But the mechanism by which cancer stem cells maintain their stemness remains unclear.In the present study, ovarian cancer stem cells (OCSCs) were revealed to have an enhanced autophagic flux. Furthermore, their chemoresistance and ability to self-renewal in vitro were decreased when autophagy was inhibited by Bafilomycin A1(BafA1), Chloroquine(CQ) or autophagy related 5(ATG5) knockdown. PCR array screening determined that Forkhead Box A2(FOXA2) was highly expressed in OCSCs, and correspondingly regulated by autophagy activity. In addition, the self-renewal ability was decreased in the case of FOXA2 knockdown by shRNA in OCSCs. Overexpression of FOXA2 from the pEGFP(+)-FOXA2 plasmid partially reversed the depressed self-renewal ability of OCSCs during autophagy inhibition.Our findings suggest that autophagy, through participation of FOXA2, maintains the characteristics of OCSCs. Autophagy and FOXA2 are therefore potential targets for ovarian cancer stem cell directed therapies.

SUBMITTER: Peng Q

PROVIDER: S-EPMC5707869 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

Peng Qiaohua Q Qin Jiale J Zhang Yanan Y Cheng Xiaodong X Wang Xinyu X Lu Weiguo W Xie Xing X Zhang Songfa S

Journal of experimental & clinical cancer research : CR 20171129 1

<h4>Background</h4>Cancer stem cells (CSCs) are regarded as the main cell type responsible for the initiation, metastasis, drug resistance, and recurrence of cancer. But the mechanism by which cancer stem cells maintain their stemness remains unclear.<h4>Methods and results</h4>In the present study, ovarian cancer stem cells (OCSCs) were revealed to have an enhanced autophagic flux. Furthermore, their chemoresistance and ability to self-renewal in vitro were decreased when autophagy was inhibite ...[more]

PMID: 29187221

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Project description:The majority of women diagnosed with epithelial ovarian cancer eventually develop recurrence, which rapidly evolves into chemoresistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy may be responsible for emergence of resistant tumors. In this study, we demonstrate that in OCSC, the tumor suppressor disabled homolog 2-interacting protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in epithelial ovarian cancer cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in ovarian cancer significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse phase protein array further demonstrated activation of noncanonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Coadministration of EZH2 inhibitor GSK126 and RAC1 inhibitor NSC23766 suppressed OCSC survival in vitro and inhibited tumor growth and increased platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent ovarian cancer recurrence and has potential for clinical translation. SIGNIFICANCE: These findings show that combining an epigenetic therapy with a noncanonical WNT signaling pathway inhibitor has the potential to eradicate ovarian cancer stem cells and to prevent ovarian cancer recurrence.

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Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

Publications

Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

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