Related Experiment Video
Updated: Feb 26, 2026
Author Spotlight: Exploring Advanced Therapeutic Targets in Osteosarcoma Through Spatial Transcriptomics
Published on: May 3, 2024
A novel interplay between HOTAIR and DNA methylation in osteosarcoma cells indicates a new therapeutic strategy
Xingang Li1, Hongming Lu2, Guilian Fan2
1Department of Orthopaedics, Heilongjiang General Hospital of Daqing Oil Field, Daqing, 163000, China.
Purpose:
Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive.
Method:
Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS.
Results:
We found that HOTAIR is highly expressed in OS cells and the knockdown of HOTAIR leads to the down-regulation of DNMT1, as well as the decrease of global DNA methylation level. RNA-sequencing analysis of HOTAIR-regulated gene shows that CDKN2A is significantly repressed by HOTAIR. A series of experiments show that HOTAIR represses the expression of CDKN2A through inhibiting the promoter activity of CDKN2A by DNA hypermethylation. Further evidence shows that HOTAIR activates the expression of DNMT1 through repressing miR-126, which is the negative regulator of DNMT1. Functionally, HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDKN2A axis.
Conclusion:
These results not only enrich our understanding of the regulation relationship between non-coding RNA, DNA methylation, and gene expression, however, also provide a novel direction in developing more sophisticated therapeutic strategies for OS patients.
Insights
This study reveals HOTAIR’s role in osteosarcoma (OS) by regulating DNA methylation via miR-126 and DNMT1, impacting CDKN2A expression and offering new therapeutic targets for OS.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Osteosarcoma (OS) is a primary bone cancer prevalent in adolescents.
- HOTAIR, a long non-coding RNA, is implicated in cancer epigenetics, particularly DNA methylation.
- The precise mechanisms linking HOTAIR, DNA methylation, and OS pathogenesis are not fully understood.
Purpose of the Study:
- To elucidate the regulatory interplay between HOTAIR, DNA methylation, and gene expression in osteosarcoma.
- To investigate the biological functions and therapeutic implications of this axis in OS.
Main Methods:
- RNA-sequencing and computational analysis were employed to identify regulatory networks.
- Experimental validations included gene knockdown, promoter activity assays, and cell viability/apoptosis studies.
- The study focused on the HOTAIR-miR-126-DNMT1-CDKN2A signaling pathway.
Main Results:
- HOTAIR is highly expressed in OS cells and its knockdown reduces DNMT1 expression and global DNA methylation.
- HOTAIR represses CDKN2A expression through DNA hypermethylation of its promoter.
- HOTAIR activates DNMT1 by downregulating miR-126, a negative regulator of DNMT1.
- HOTAIR depletion sensitizes OS cells to DNMT1 inhibitors by modulating viability and apoptosis.
Conclusions:
- This study uncovers a novel regulatory axis (HOTAIR-miR-126-DNMT1-CDKN2A) in osteosarcoma.
- Findings enhance the understanding of non-coding RNA and DNA methylation interactions in gene regulation.
- The identified pathway presents a promising therapeutic strategy for osteosarcoma treatment.
