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EHMT2 Suppresses ARRB1 Transcription and Activates the Hedgehog Signaling to Promote Malignant Phenotype and Stem Cell Property in Oral Squamous Cell Carcinoma

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Abstract

Oral squamous cell carcinoma (OSCC) represents the primary subtype of head and neck squamous cell carcinoma (HNSCC), characterized by a high morbidity and mortality rate. Although previous studies have established specific correlations between euchromatic histone lysine methyltransferase 2 (EHMT2), a histone lysine methyltransferase, and the malignant phenotype of OSCC cells, its biological functions in OSCC remain largely unknown. This study, grounded in bioinformatics predictions, aims to clarify the influence of EHMT2 on the malignant behavior of OSCC cells and delve into the underlying mechanisms. EHMT2 exhibited high expression in OSCC tissues and demonstrated an association with poor patient outcomes. Artificial EHMT2 silencing in OSCC cells, achieved through lentiviral vector infection, significantly inhibited colony formation, migration, invasion, and cell survival. Regarding the mechanism, EHMT2 was found to bind the promoter of arrestin beta 1 (ARRB1), thereby suppressing its transcription through H3K9me2 modification. ARRB1, in turn, was identified as a negative regulator of the Hedgehog pathway, leading to a reduction in the proteins GLI1 and PTCH1. Cancer stem cells (CSCs) were enriched through repeated sphere formation assays in two OSCC cell lines. EHMT2 was found to activate the Hedgehog pathway, thus promoting sphere formation, migration and invasion, survival, and tumorigenic activity of the OSCC-CSCs. Notably, these effects were counteracted by the additional overexpression of ARRB1. In conclusion, this study provides novel evidence suggesting that EHMT2 plays specific roles in enhancing stem cell properties in OSCC by modulating the ARRB1-Hedgehog signaling cascade.

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Data and Materials Availability

All the data generated or analyzed during this study are included in this published article.

Abbreviations

ANOVA:

Analysis of variance

ARRB1:

Arrestin beta 1

CSCs:

Cancer stem cells

ChIP:

Chromatin immunoprecipitation

DEGs:

Differentially expressed genes

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulphoxide

EHMT2:

Euchromatic histone lysine methyltransferase 2

FBS:

Fetal bovine saline

HNSCC/HNSC:

Head and neck squamous cell carcinoma

H3K9me2:

Histone 3 lysine 9 di-methylation

IHC:

Immunohistochemistry

KEGG:

Kyoto Encyclopedia of Genes and Genomes

NC:

Negative control

OSCC:

Oral squamous cell carcinoma

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

SAG:

Smoothened agonist

shRNA:

Short hairpin RNA

TUNEL:

Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling

ve-:

Overexpression (of certain genes)

WB:

Western blot

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Funding

This work was supported by Science and Technology Research Project of Jilin Provincial Department of Education (No. JJKH20230084KJ).

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Authors and Affiliations

  1. Department of Stomatology, Affiliated Hospital of Beihua University, No. 3999, Binjiang East Road, Fengman District, Jilin, 132011, Jilin, People’s Republic of China

    Ling Niu & Guangyao Hu

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  1. Ling Niu
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  2. Guangyao Hu
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Correspondence to Guangyao Hu.

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Ethical Statement

The study protocol was approved by the Institutional Review Board of Affiliated Hospital of Beihua University. All patients had complete clinical information and signed the informed consent. All procedures were performed in adherence to the principles of Declaration of Helsinki. Animal experiments were conducted following the protocol approved by the Animal Ethics Committee of Affiliated Hospital of Beihua University.

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Supplementary Information

Below is the link to the electronic supplementary material.

12033_2024_1130_MOESM1_ESM.pdf

Supplementary file1 (PDF 51227 KB) Bioinformatics analyses of DEGs and their prognostic values in OSCC. A Volcano plots for DEGs between OSCC and normal samples in GSE56532, GSE30784, and GSE10121 datasets; B intersections of three sets of significantly DEGs (adj. p value < 0.05), human transcription factors or co-factors retrieved from the Human TFBD system, and top 2000 OSCC-related genes retrieved from the GeneCards system; C, D further analyses of genes showing consistent upregulation (C) or downregulation (D) patterns in GSE56532, GSE30784, and GSE10121 datasets; E protein–protein interaction analysis of intersecting genes in panels C and D; F prognostic significances of AURKB, BIRC5, CCNA2, CDK2, CHUK, CREBBP, EHMT2, FOXM1, PML, RELB, and STAT1 in HNSC in the Kaplan–Meier Plotter system; G expression profile of the EHMT2 in HNSC and normal cohorts in the StarBase system

12033_2024_1130_MOESM2_ESM.pdf

Supplementary file2 (PDF 500 KB) Bioinformatics analyses of downstream target of EHMT2. A Intersections of target transcripts of EHMT2 and the three sets of DEGs identified using GSE56532, GSE30784, and GSE10121 datasets; B, C KEGG pathway enrichment analysis of the 94 intersecting genes; D ARRB1 as a transcription target of EHMT2 in the hTFtarget system; E expression of ARRB1 in HNSC and normal cohorts in the StarBase system; F binding peaks between EHMT2 and ARRB1 promoter predicted in the ChIP-seq database

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Niu, L., Hu, G. EHMT2 Suppresses ARRB1 Transcription and Activates the Hedgehog Signaling to Promote Malignant Phenotype and Stem Cell Property in Oral Squamous Cell Carcinoma. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01130-9

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