Guilu erxian glue alleviates chemotherapy-induced myelosuppression by regulating histone methylation level of p16 gene in hematopoietic stem cells

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Background: Myelosuppression is a common chemotherapy-related toxicity and hematopoietic stem cells (HSCs) senescence is the main mechanism. Guilu Erxian Glue (GEG) is an effective Chinese herbal prescription for the treatment of myelosuppression in clinical, the potential mechanism needs further investigation. Objective: To explore the protective effect of GEG on HSCs during chemotherapy-induced myelosuppression and its mechanism. Methods: Eighteen H22 hepatoma-bearing mice were divided equally into three groups: control, cisplatin (DDP), and DDP+GEG groups. Peripheral blood cell counts and bone marrow nucleated cell counts were performed. Bone marrow histopathology was assessed by hematoxylin and eosin (H&E) staining. DNA damage was assessed by γ-H2AX immunofluorescence staining. The serum containing GEG was prepared for in vitro experiments. Superoxide dismutase (SOD) activity, cell viability , cell cycle, and aging cells were detected in vivo and in vitro . In addition, western blot , quantitative reverse transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation (CHIP) assay were applied to explore the molecular mechanism. Results: GEG administration resulted in a significant increase in peripheral blood cells and bone marrow nucleated cells ( P < 0.01), and improved the pathological histomorphology of bone marrow. Treatment with GEG or silencing of the p16 Ink4a gene enhanced the SOD activity and viability of HSCs, while reducing DDP-induced DNA damage, G2-M cell cycle arrest and senescent cell formation ( P < 0.001). GEG decreased both mRNA and protein levels of p16, while increased the protein and mRNA expression levels of CDK4, CDK6, and pRb both in vivo and in vitro experiments ( P < 0.05). ChIP-qPCR showed that the p16 Ink4a promoter region was enriched with JMJD2 and H3K36me2/me3 protein. GEG treatment up-regulated the protein and mRNA expression levels of JMJD2 and simultaneously down-regulated H3K36me2/me3 protein levels. Conclusion: Our findings suggest that GEG exerts regulatory effects on p16 Ink4a gene expression through modulating the levels of H3K36 methylation . This study provides important mechanistic insights into the effects of GEG on HSCs and suggests potential therapeutic applications for GEG in myelosuppression.

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