Promotion of colorectal cancer progression by immune-related lnc-SOX9-4 via suppression of YBX1 poly-ubiquitination and degradation

Yan Zhao; Sheng Yang; Hongxu Nie; Dongsheng Zhang; Tuo Wang; Qingyang Sun; Xiaowei Wang; Yueming Sun

doi:10.1016/j.cellsig.2023.110854

Promotion of colorectal cancer progression by immune-related lnc-SOX9-4 via suppression of YBX1 poly-ubiquitination and degradation

Cell Signal. 2023 Nov:111:110854. doi: 10.1016/j.cellsig.2023.110854. Epub 2023 Aug 22.

Authors

Yan Zhao¹, Sheng Yang², Hongxu Nie², Dongsheng Zhang³, Tuo Wang², Qingyang Sun², Xiaowei Wang³, Yueming Sun⁴

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China.
² Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China.
³ Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China.
⁴ Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China. Electronic address: sunyueming@njmu.edu.cn.

PMID: 37611648
DOI: 10.1016/j.cellsig.2023.110854

Abstract

Background: Recent research has highlighted the versatile functions of long non-coding RNAs (lncRNAs) in the onset and progression of various malignancies. Still, insufficient knowledge is available on how lnc-SOX9-4 functions in colorectal cancer (CRC) progression.

Methods: Bioinformatics analysis was used to identify a novel lncRNA (lnc-SOX9-4), and the expression pattern of the RNA in CRC was verified using qRT-PCR. Gene ontology (GO) term analysis and Gene set enrichment analysis (GSEA) were implemented for the identification of the related mechanisms and roles of lnc-SOX9-4. Immune infiltration analysis was conducted for assessment of how lnc-SOX9-4 is linked to tumor immune cell infiltration level. Both in vitro and in vivo phenotype analyses were conducted for scrutinizing how lnc-SOX9-4 impacts the proliferation and metastasis of CRC. RNA pulldown, mass spectrometry analysis, fluorescent in situ hybridization (FISH), western blotting, and RIP assay aided in verifying lnc-SOX9-4 mechanisms linked to CRC progression.

Results: An upregulation of lnc-SOX9-4 was observed in the sample CRC cells and tissues. Elevated lnc-SOX9-4 levels showed a positive association with poor clinical prognosis. Lnc-SOX9-4 was closely correlated to several types of immune infiltrating cells. Functionally, the knockdown of lnc-SOX9-4 significantly inhibited CRC cell proliferation, migration, and invasion abilities. Mechanistically, YBX1 was identified as lnc-SOX9-4, specifically interacting protein in the nucleus. Lnc-SOX9-4 could stabilize YBX1 protein levels by inhibiting poly-ubiquitination and degradation of YBX1. Furthermore, phenotype rescue experiments reveal that lnc-SOX9-4 enhanced the CRC cellular potential to proliferate and metastasize by regulating YBX1 levels.

Conclusions: Lnc-SOX9-4 promoted CRC progression by suppressing cytoplasmic translocation and promoting protein levels of YBX1 can serve as novel treatment targets for diagnosing and treating CRC.

Keywords: CRC progression; Lnc-SOX9–4; Oncogene; Tumor immune microenvironment; Ubiquitination and degradation; YBX1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Colorectal Neoplasms* / pathology
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
RNA / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
SOX9 Transcription Factor / genetics
SOX9 Transcription Factor / metabolism
Ubiquitination
Y-Box-Binding Protein 1 / genetics
Y-Box-Binding Protein 1 / metabolism

Substances

RNA
RNA, Long Noncoding
YBX1 protein, human
Y-Box-Binding Protein 1
SOX9 protein, human
SOX9 Transcription Factor