LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer

Meng Yue,Xiaofan Luo,Lei Wang,Tao Liu,Guoqiang Yan

doi:10.1186/s12935-021-02180-8

Meng Yue, Xiaofan Luo + Show 3 more

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https://doi.org/10.1186/s12935-021-02180-8

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Abstract

BackgroundColorectal cancer (CC) is one of the major contributors to tumor-related death worldwide, and its main cause of death is distant metastasis. Dysregulation of long non-coding RNA (lncRNA) LINC01605 has been implicated in CC. However, its role in metastasis of CC remains elusive. The goal of the study is to uncover the biological function and molecular mechanism of LINC01605 in CC.MethodsThe differentially expressed lncRNAs were first screened from GSE97300, GSE84983, GSE110715, GSE70880, and GSE75970 microarrays. The correlation between the expression of LINC01605 and the clinical phenotypes of enrolled CC patients (n = 134) was subsequently analyzed. The upstream and downstream regulatory mechanisms of LINC01605 in CC were identified through bioinformatics and RNA-seq analyses. Finally, the effects of related factors on CC cell growth and metastasis were confirmed through functional validation experiments.ResultsLINC01605, significantly highly expressed in CC, was a prognostic factor for patients with CC. Functional experiments revealed that LINC01605 knockdown inhibited the proliferatory and metastatic potential of CC cells in vitro and in vivo. Moreover, LINC01605 was regulated by SMYD2-EP300-mediated modifications of histone H3K4me3 as well as H3K27ac. LINC01605 was found to bind to METTL3 and promote the m6A modification of SPTBN2 mRNA, thereby facilitating the translation of SPTBN2.ConclusionsOverexpression of LINC01605, regulated by SMYD2-EP300-mediated H3K27ac and H3K4me3 modifications, bound to METTL3 protein to promote m6A modification of SPTBN2 mRNA, leading to the development of CC.

Highlights

Colorectal cancer (CC) is one of the major contributors to tumor-related death worldwide, and its main cause of death is distant metastasis
We further found that increasing the expression of SET and MYND domain-containing protein 2 (SMYD2) or E1A binding protein p300 (EP300) in the cells significantly enhanced the proliferative activity of the cells (Fig. 5E), which was accompanied by a significant decrease in the proportion of apoptotic cells and the number of apoptosis bodies (Fig. 5F, G)
Combined with our findings derived from the immunohistochemistry and chromatin immunoprecipitation (ChIP)-qPCR, we corroborated that the overexpression of LINC01605 in CC was caused by the aberrant modification of H3K27ac and H3K4me3

Summary

Introduction

Colorectal cancer (CC) is one of the major contributors to tumor-related death worldwide, and its main cause of death is distant metastasis. Dysregulation of long non-coding RNA (lncRNA) LINC01605 has been implicated in CC. Long non-coding RNAs (lncRNAs) are identified as significant contributors to the initiation, progression and metastasis of CC [3]. Histone H3 on lysine 27 acetylation (H3K27ac), another class of histone posttranslational modification, is frequently linked to the active enhancer regulatory elements, contributing to the upregulation of genes [6]. Our preliminary prediction revealed significant H3K4me and H3K27ac modifications near the promoter of LINC01605. We postulated that the upregulation of LINC01605 was due to the H3K4me and H3K27ac modifications

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