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LncRNA LENGA acts as a tumor suppressor in gastric cancer through BRD7/TP53 signaling

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Abstract

It has been established that long noncoding RNAs (lncRNAs) play a crucial role in various cancer types, and there are vast numbers of long noncoding RNA transcripts that have been identified by high-throughput methods. However, the biological function of many novel aberrantly expressed lncRNAs remains poorly elucidated, especially in gastric cancer (GC). Here, we first identified a novel lncRNA termed LENGA (Low Expression Noncoding RNA in Gastric Adenocarcinoma), which was significantly downregulated in GC tissues compared to adjacent normal tissues. Next, we found that reduced expression of LENGA in GC was also associated with a shorter life expectancy. The proliferation, migration, and invasion of GC cells were increased after LENGA knockdown but restrained after LENGA overexpression in vitro and in vivo. It was further demonstrated that LENGA physically binds to BRD7 (bromodomain-containing 7) in the bromodomain domain and acts as a scaffold that enhances the interaction between BRD7 and TP53 (tumor protein p53), regulating the expression of a subset of genes in the p53 pathway, including CDKN1A (cyclin-dependent kinase inhibitor 1A) and PCDH7 (protocadherin 7), at the transcriptional level. Consistently, the expression of CDKN1A has a positive correlation with LENGA in GC patients. Taken together, this study uncovers a novel tumor suppressor lncRNA, LENGA, and describes its biological function, molecular mechanism, and clinical significance. This highlights the potential importance of targeting the LENGA/BRD7/TP53 axis in GC treatment.

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Availability of data and materials

All data that support the findings of this study are available from the corresponding author upon reasonable request. High-throughput sequence data of RNA-seq and CUT&Tag was deposited in NCBI, GEO (GSE189471).

Abbreviations

lncRNA:

Long noncoding RNA

GC:

Gastric cancer

LENGA:

Low Expression Noncoding RNA in Gastric Adenocarcinoma

BRD7:

Bromodomain-containing 7

TP53:

Tumor protein p53

CDKN1A:

Cyclin-dependent kinase inhibitor 1A

STR:

Short tandem repeat

GSPs:

Gene-specific primers

RIP:

RNA immunoprecipitation

SPF:

Specific pathogen-free

GEO:

Gene Expression Omnibus

TCGA:

The Cancer Genome Atlas

NCBI:

National Center for Biotechnology Information

RACE:

Rapid amplification of cDNA ends

FISH:

Fluorescent in situ hybridization

CCK-8:

Cell Counting Kit-8

4s1m:

4 × Streptavidin-binding RNA aptamer

MS:

Mass spectrometry

FL:

Full-length

CUT&Tag:

Cleavage Under Targets and Tagmentation

GSEA:

Gene set enrichment analysis

SWI/SNF:

Switch/Sucrose Non-Fermentable complex

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (NSFC) (Grant nos. 81871984, 81772831, 82072614), Advanced and Appropriate Technology Promotion Project of Shanghai Health Commission (Grant no. 2019SY030), Shanghai Municipal Key Clinical Specialty (Grant No. shslczdzk00102) and Shanghai Jiao Tong University School of Medicine “Two-hundred Talent” team (Grant no. RC20200026). We are grateful to Prof. Ming He for the discussion, and Dr. Li Xia and his team in the core facility of basic medical science (Shanghai Jiao Tong University School of Medicine) for excellent support in MS.

Funding

This work is supported by the National Natural Science Foundation of China (NSFC) (Grant nos. 81871984, 81772831, 82072614), Advanced and Appropriate Technology Promotion Project of Shanghai Health Commission (Grant no. 2019SY030), Shanghai Municipal Key Clinical Specialty (Grant no. shslczdzk00102) and Shanghai Jiao Tong University School of Medicine “Two-hundred Talent” team (Grant no. RC20200026).

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Author notes

  1. Shuchun Li and Jing Sun contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Shuchun Li, Jing Sun, Junjun Ma, Xiao Yang, Sen Zhang, Ling Huang, Hongtao Jia, Yanfei Shao, Enkui Zhang, Minhua Zheng & Lu Zang

  2. Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jing Sun, Junjun Ma, Xiao Yang, Sen Zhang, Ling Huang, Hongtao Jia, Yanfei Shao, Enkui Zhang, Minhua Zheng & Lu Zang

  3. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Shuchun Li, Cixiang Zhou & Qian Zhao

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  1. Shuchun Li
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Contributions

Conception and design: LZ, QZ, MZ; methodology: SL, CZ, LH, SZ; acquisition of data (provided animals, acquired, and managed patients): SZ, LH, JM; analysis and interpretation of data (e.g., statistical analysis, biostatistics analysis): XY, YS, HJ, EZ; supervision: MZ, LZ; funding acquisition: LZ, QZ, MZ, JS; writing, review, or revision of the manuscript: SL, QZ, LZ, JS.

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Correspondence to Minhua Zheng, Qian Zhao or Lu Zang.

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Li, S., Sun, J., Ma, J. et al. LncRNA LENGA acts as a tumor suppressor in gastric cancer through BRD7/TP53 signaling. Cell. Mol. Life Sci. 80, 5 (2023). https://doi.org/10.1007/s00018-022-04642-2

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