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Published on: February 1, 2020
LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC
Luyuan Ma1,2, An Xu3, Lei Kang4
1Department of Infectious Diseases, the Third Hospital of Hebei Medical University, Shijiazhuang, China.
Background And Aims:
Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently.
Methods:
RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance.
Results:
LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression.
Conclusions:
LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.
Insights
This study identifies the LSD1/LINC01134/SP1/p62 axis as crucial for oxaliplatin resistance in hepatocellular carcinoma (HCC). Measuring LINC01134 levels can predict treatment efficacy and guide therapeutic strategies.
Area of Science:
- Molecular Oncology
- Cancer Biology
- Genomics
Background:
- Hepatocellular carcinoma (HCC) treatment often involves oxaliplatin (OXA), but resistance is a significant clinical challenge.
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in modulating cancer cell response to chemotherapy.
- Understanding the mechanisms of OXA resistance and identifying predictive biomarkers are critical for improving patient outcomes.
Purpose of the Study:
- To investigate the role of lncRNAs in OXA resistance in HCC.
- To identify specific lncRNAs that predict OXA efficacy.
- To elucidate the molecular mechanisms underlying OXA resistance involving identified lncRNAs.
Main Methods:
- RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) to identify OXA-resistant lncRNAs.
- Survival analysis to assess the clinical significance of LINC01134 and p62.
- In vitro assays (luciferase, RIP, ChIP, ChIRP) to explore regulatory mechanisms.
- In vitro and in vivo (xenografts) experiments to evaluate the functional impact of the LINC01134/SP1/p62 axis on OXA resistance.
Main Results:
- Homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) was significantly upregulated in OXA-resistant HCC cells.
- Higher LINC01134 expression correlated with poorer OXA treatment outcomes.
- LINC01134 promotes OXA resistance by recruiting SP1 to the p62 promoter, activating an anti-oxidative pathway.
- Lysine specific demethylase 1 (LSD1) was identified as the demethylase responsible for LINC01134 upregulation.
- Positive correlations were observed between LINC01134, p62, and LSD1 in HCC patients.
Conclusions:
- The LSD1/LINC01134/SP1/p62 axis is a key determinant of OXA resistance in HCC.
- LINC01134 expression serves as a predictive biomarker for OXA efficacy in HCC patients.
- Targeting the LINC01134/SP1/p62 axis presents a potential therapeutic strategy to overcome OXA chemoresistance.
