Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression

Yen Sung Huang, Che Chang Chang, Szu Shuo Lee, Yuh Shan Jou, Hsiu Ming Shih

研究成果: 雜誌貢獻文章

53 引文 (Scopus)

摘要

Long noncoding RNAs (lncRNAs) dysregulated in cancer potentially play oncogenic or tumor-suppressive roles. While the X inactivate-specific transcript (Xist) lncRNA is important for X-chromosome inactivation in female cells, very little is known about the role of Xist in human breast cancer in modulating cellular pathway(s). Here, we show that Xist expression is significantly reduced in breast tumor samples and cancer cell lines. Xist knockdown or overexpression resulted in increased or decreased levels, respectively, of AKT phosphorylation and cell viability. Further studies revealed an inverse correlation between Xist and phospho-AKT levels in breast cancer samples. Additionally, Xist knockdown-elicited increase of cell viability was attenuated by AKT inhibitor. These results suggest that Xist negatively regulates cell viability via inhibition of AKT activation. Interestingly, decreased Xist expression in breast cancer samples was associated with reduced levels of Jpx RNA, an lncRNA that positively regulates Xist promoter activity. Accordingly, Jpx knockdown enhanced AKT activation and cell viability. We also demonstrate that knockdown of Xist or SPEN, an intermediator protein to link Xist, SMRT co-repressor and HDAC3 complexes for X-chromosome inactivation, decreased expression of PHLPP1, a phosphatase to remove AKT phosphorylation, via increased HDAC3 recruitment to the PHLPP1 promoter, correlating with increased AKT phosphorylation. Our findings elucidate the tumor suppressor role of Xist in breast cancer and provide the molecular basis of Xist in downregulating AKT activation.
原文英語
頁(從 - 到)43256-43266
頁數11
期刊Oncotarget
7
發行號28
DOIs
出版狀態已發佈 - 2016

指紋

Up-Regulation
Phosphorylation
Long Noncoding RNA
Breast Neoplasms
Cell Survival
X Chromosome Inactivation
Nuclear Receptor Co-Repressor 2
Neoplasms
Phosphoric Monoester Hydrolases
Down-Regulation
RNA
Cell Line

ASJC Scopus subject areas

  • Oncology

引用此文

Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression. / Huang, Yen Sung; Chang, Che Chang; Lee, Szu Shuo; Jou, Yuh Shan; Shih, Hsiu Ming.

於: Oncotarget, 卷 7, 編號 28, 2016, p. 43256-43266.

研究成果: 雜誌貢獻文章

Huang, Yen Sung ; Chang, Che Chang ; Lee, Szu Shuo ; Jou, Yuh Shan ; Shih, Hsiu Ming. / Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression. 於: Oncotarget. 2016 ; 卷 7, 編號 28. 頁 43256-43266.
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abstract = "Long noncoding RNAs (lncRNAs) dysregulated in cancer potentially play oncogenic or tumor-suppressive roles. While the X inactivate-specific transcript (Xist) lncRNA is important for X-chromosome inactivation in female cells, very little is known about the role of Xist in human breast cancer in modulating cellular pathway(s). Here, we show that Xist expression is significantly reduced in breast tumor samples and cancer cell lines. Xist knockdown or overexpression resulted in increased or decreased levels, respectively, of AKT phosphorylation and cell viability. Further studies revealed an inverse correlation between Xist and phospho-AKT levels in breast cancer samples. Additionally, Xist knockdown-elicited increase of cell viability was attenuated by AKT inhibitor. These results suggest that Xist negatively regulates cell viability via inhibition of AKT activation. Interestingly, decreased Xist expression in breast cancer samples was associated with reduced levels of Jpx RNA, an lncRNA that positively regulates Xist promoter activity. Accordingly, Jpx knockdown enhanced AKT activation and cell viability. We also demonstrate that knockdown of Xist or SPEN, an intermediator protein to link Xist, SMRT co-repressor and HDAC3 complexes for X-chromosome inactivation, decreased expression of PHLPP1, a phosphatase to remove AKT phosphorylation, via increased HDAC3 recruitment to the PHLPP1 promoter, correlating with increased AKT phosphorylation. Our findings elucidate the tumor suppressor role of Xist in breast cancer and provide the molecular basis of Xist in downregulating AKT activation.",
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