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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma
Xing Bao1,2, Tingting Ren1,2, Yi Huang1,2
1Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.
Abstract:
Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma.
Insights
Long non-coding RNA HOTAIR is upregulated in chondrosarcoma, inhibiting cell death pathways. Silencing HOTAIR shows therapeutic potential by promoting apoptosis and reducing autophagy in chondrosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Current chondrosarcoma therapies are insufficient.
- Long non-coding RNAs (lncRNAs) are implicated in tumor development.
- HOTAIR, a lncRNA, is overexpressed in many cancers but its role in chondrosarcoma is unclear.
Purpose of the Study:
- To investigate the function and molecular mechanisms of HOTAIR in human chondrosarcoma.
- To determine if HOTAIR can serve as a prognostic biomarker or therapeutic target.
Main Methods:
- Quantitative RT-PCR to measure HOTAIR expression.
- In vitro and in vivo functional experiments involving HOTAIR knockdown.
- Analysis of cell cycle, apoptosis, and autophagy.
- Investigation of the epigenetic regulation of miR-454-3p by HOTAIR, EZH2, and DNMT1.
- Identification of miR-454-3p targets (STAT3 and ATG12).
Main Results:
- HOTAIR expression is upregulated in chondrosarcoma tissues and cell lines.
- High HOTAIR expression correlates with advanced tumor stage and poor prognosis.
- HOTAIR knockdown inhibits chondrosarcoma cell growth, induces cell cycle arrest and apoptosis, and suppresses autophagy.
- HOTAIR epigenetically silences miR-454-3p by recruiting EZH2 and DNMT1.
- miR-454-3p targets STAT3 and ATG12, mediating HOTAIR's effects on apoptosis and autophagy.
Conclusions:
- HOTAIR plays a crucial role in chondrosarcoma progression.
- HOTAIR promotes tumor growth by silencing miR-454-3p, which in turn affects apoptosis and autophagy.
- HOTAIR represents a potential prognostic biomarker and therapeutic target for chondrosarcoma.
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