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

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.

High Expression of LINC01420 indicates an unfavorable prognosis and modulates cell migration and invasion in nasopharyngeal carcinoma

“…Studies demonstrated that Xist directly interacts with SHARP to silence transcription through HDAC3 51 and the histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression 52. While another research reported that Xist reduction in breast cancer upregulated AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression 53. Xist also play important role in cervical cancer 54, non-small cell lung cancer 55 glioblastoma 56 and so on.…”

Long Intergenic Noncoding RNA 00511 Acts as an Oncogene in Non–small-cell Lung Cancer by Binding to EZH2 and Suppressing p57

“…Immunohistochemistry of the tumor tissues was performed as described previously. 35,36,37 3-μm tumor sections were incubated with commercial rabbit polyclonal antibodies against Ki67 (Santa Cruz), p57 (Santa Cruz) at 1/100 dilution overnight at 4 °C. Then, the sections were conjugated with horseradish peroxidase antibody (1:500 dilution; Santa Cruz Biotechnology, Santa Cruz, CA) at room temperature for 2 hours, then covered by diaminobenzidine (DAB) (Vector Laboratories, Burlingame, CA), and slides were mounted with Vectashield mounting medium (Vector Laboratories).…”

“…Long intergenic noncoding RNA 00511 (LINC00511, NR 033876), is a newly identified lncRNA that is upregulated in human breast cancer, 36 which may serve as an oncogene. Nevertheless, biological roles and underlying molecular mechanisms of LINC00511 in NSCLC tumorigenesis are still remaining unclearly defined.…”

The Long Non-Coding RNA XIST Controls Non-Small Cell Lung Cancer Proliferation and Invasion by Modulating miR-186-5p

“…XIST is highly expressed in some carcinomas including breast cancer [13], glioblastoma [14] and ovarian cancer [15], suggesting that XIST may serve as a biomarker for the diagnosis of these cancers. A recent study showed that XIST is upregulated and is essential for the long term survival of NSCLC [16]; however, its molecular role in NSCLC has not been clarified.…”