The DPY30-H3K4me3 Axis-Mediated PD-L1 Expression in Melanoma

Zhichun Zhang; Yixuan Han; Qiuyue Sun; Yipeng Wang; Lichao Sun

doi:10.2147/JIR.S377678

The DPY30-H3K4me3 Axis-Mediated PD-L1 Expression in Melanoma

J Inflamm Res. 2022 Sep 26:15:5595-5609. doi: 10.2147/JIR.S377678. eCollection 2022.

Authors

Zhichun Zhang¹, Yixuan Han², Qiuyue Sun¹, Yipeng Wang³, Lichao Sun⁴

Affiliations

¹ Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
² Department of Rheumatology and Immunology, Affiliated Kailuan General Hospital of North China University of Science and Technology, Tangshan, People's Republic of China.
³ Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
⁴ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.

Abstract

Background: DPY30 is a common subunit of the human SET1/MLL complex and is an essential protein required for the activity of SET1/MLL methyltransferase. DPY30 regulates the histone H3K4 modification, and dysfunction of DPY30 might contribute to the regulation of cancer immune evasion. However, the functions and regulation of DPY30 in the expression of programmed cell death ligand 1 (PD-L1) is still not completely explored.

Methods: Various online databases were used for data processing and visualization, including UALCAN, Oncomine, cBioPortal, SangerBox, TISIDB, TIMER, and GEPIA databases. The expression of DPY30 and PD-L1 in melanoma tissues were evaluated by IHC. Chromatin Immunoprecipitation (ChIP), RT-PCR and flow cytometry were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation and its function.

Results: The mRNA level of DPY30 in melanoma was higher than in normal tissues. The expression of DPY30 was positively associated with TMB, neoantigens and PD-L1 expression. Furthermore, DPY30 expression showed significant positive correlations with immune suppressor cells and ICP genes involved in T-cell exhaustion. IHC showed that the positive rates of DPY30 and PD-L1 in melanoma tissues were 62% and 58%, respectively. Correlation analysis revealed that DPY30 over-expression was positively associated with PD-L1 expression. Silencing of DPY30 by specific siRNA significantly inhibited PD-L1 expression. ChIP analysis revealed that H3K4me3 levels were enriched in the proximal PD-L1 promoter region in tumor cells. Inhibition of DPY30 still suppressed the PD-L1 level in IFN-γ treated MMAC-SF cells. Furthermore, the apoptosis of PD1⁺ T-cells in co-culture with MMAC-SF cells by knockdown of DPY30 were markedly reduced.

Conclusion: This study shows the roles of DPY30 in regulating the cancer immune evasion in melanoma. Targeting the DPY30-H3K4me3 axis might be an alternative approach to enhance the efficacy of checkpoint immunotherapy.

Keywords: DPY-30; H3K4me3; PD-L1; immunotherapy; melanoma.

Grants and funding

This research was supported by the Xi Wang Zhi Xing Project of National Cancer Center.