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Chromosomal copy number amplification-driven Linc01711 contributes to gastric cancer progression through histone modification-mediated reprogramming of cholesterol metabolism

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Abstract

Background

Chromosome gains or localized amplifications are frequently observed in human gastric cancer (GC) and are major causes of aberrant oncogene activation. However, the significance of long non-coding RNAs (LncRNAs) in the above process is largely unknown.

Methods

The copy number aberrations (CNAs) data of GC samples were downloaded and analyzed from the TCGA database. qRT-PCR and fluorescence in situ hybridization were used to evaluate the expression of Linc01711 in GC. The effects of Linc01711 on GC progression were investigated through in vitro and in vivo assays. The mechanism of Linc01711 action was explored through transcriptome sequencing, chromatin immunoprecipitation sequencing, RNA immunoprecipitation, RNA pull-down and chromatin isolation by RNA purification (ChIRP) assays.

Results

We report for the first time a novel DNA copy number amplification-driven LncRNA on chromosome 20q13, designated Linc01711 in human GC, which is highly associated with malignant features. Functionally, Linc01711 significantly accelerates the proliferation and metastasis of GC. Mechanistically, Linc01711 acts as a modular scaffold to promote the binding of histone acetyltransferase HBO1 and histone demethylase KDM9. By coordinating the localization of the HBO1/KDM9 complex, Linc01711 specifies the histone modification pattern on the target genes, such as LPCAT1, and consequently facilitates the cholesterol synthesis, thereby contributing to tumor progression.

Conclusions

Our findings suggest that copy number amplification-driven Linc01711 may serve as a promising prognostic predictor for GC patients and targeting Linc01711-related cholesterol metabolism pathway may be meaningful in anticancer strategies.

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Data availability

All data are available upon request.

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Acknowledgements

This work was supported by the Natural Science Foundation of Shanghai (No.22ZR1438800) and “Clinic Plus” Outstanding Project of Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine (No.2020ZYA008).

Funding

Natural Science Foundation of Shanghai, 22ZR1438800, Chunchao Zhu, “Clinic Plus” Outstanding Project of Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, 2020ZYA008, Ben Yue

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Author notes

  1. Ben Yue, Jianjun Chen, and Tianshang Bao contributed equally to this work.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China

    Ben Yue, Jianjun Chen, Tianshang Bao, Yuanruohan Zhang, Linxi Yang, Zizhen Zhang, Zheng Wang & Chunchao Zhu

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  1. Ben Yue
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Contributions

Ben Yue: funding acquisition, validation, writing—original draft. Jianjun Chen: conceptualization, software, visualization. Tianshang Bao: software, validation, formal analysis. Yuanruohan Zhang: investigation. Linxi Yang: investigation. Zizhen Zhang: resources, writing—review and editing. Zheng Wang: conceptualization, resources, writing—review and editing. Chunchao Zhu: resources, funding acquisition.

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Correspondence to Chunchao Zhu.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, and performed in accordance with the Guidelines for Welfare of Animals in Experimental Neoplasia. All the sample studies were performed following written consent from all patients.

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Yue, B., Chen, J., Bao, T. et al. Chromosomal copy number amplification-driven Linc01711 contributes to gastric cancer progression through histone modification-mediated reprogramming of cholesterol metabolism. Gastric Cancer 27, 308–323 (2024). https://doi.org/10.1007/s10120-023-01464-4

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