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Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1

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Abstract

Background

Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear.

Methods

We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed.

Results

The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D.

Conclusions

KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants.

Abbreviations

ENKTL:

extranodal natural killer/T cell lymphoma

HMT:

histone methyltransferase

FFPE:

formalin-fixed paraffin-embedded

H3K4me1/2/3:

monomethylation, dimethylation or trimethylation of histone 3 lysine 4

SGK1 :

serum- and glucocorticoid-inducible kinase-1

SOCS1 :

suppressor of cytokine signaling-1

EBV:

Epstein–Barr virus

WHO:

World Health Organization

FBS:

foetal bovine serum

MOI:

multiplicity of infection

NC:

negative control

DAB:

diaminobenzidine

BCA:

bicinchoninic acid

PVDF:

polyvinylidene difluoride

ECL:

electrochemiluminescence

CCK8:

Cell Counting Kit-8

KEGG:

Kyoto Encyclopedia of Genes and Genomes

χ2 :

chi-square

OS:

overall survival

SEM:

standard error of the mean

PTCL-NOS:

peripheral T cell lymphoma, not otherwise specified

GC:

germinal center

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Acknowledgements

Not applicable.

Funding

This study was financially supported by the national natural science foundation of China (81900197, 81272626) and the Science and Technology Program of Sichuan Province (2020YJ0104).

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  1. Yue-Hua Zhang and Li-Min Gao are co-first authors.

Authors and Affiliations

  1. Department of Pathology, West China Hospital of Sichuan University, Chengdu, China

    Yue-Hua Zhang, Qing Tao, Wen-Yan Zhang, Sha Zhao, Wei-Ping Liu & Li-Min Gao

  2. Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

    Yue-Hua Zhang

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Contributions

YHZ and QT designed the study, analyzed and interpreted the data; YHZ and LMG were major contributors to writing the manuscript. WYZ and SZ revised the manuscript. WPL and LMG were responsible for the acquisition of data and institutional review board application, and gave final approval for the version to be published. All authors read and approved the final manuscript.

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Correspondence to Wei-Ping Liu or Li-Min Gao.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The Medical Ethics Committee of West China Hospital of Sichuan University approved this study (registration number: WCH2019-00121). All recruited patients gave written informed consent following the Declaration of Helsinki.

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Zhang, YH., Tao, Q., Zhang, WY. et al. Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1. Genes Genom 46, 203–212 (2024). https://doi.org/10.1007/s13258-023-01434-1

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