Sodium butyrate supresses malignant human mast cell proliferation, downregulates expression of KIT and promotes differentiation

Abstract

Sodium butyrate (NaBu) is a class I histone deacetylase inhibitor (HDACi) that can impede the proliferation of transformed cells. Although some HDACi downregulate the expression of the stem cell factor receptor (KIT/CD117), the effect of NaBu on KIT expression and human mast cell proliferation requires further elucidation. In this study, we examined the effects of NaBu on three transformed human mast cell lines, HMC-1.1, HMC-1.2 and LAD2. NaBu (100 µM) inhibited the proliferation and metabolic activity of all three cell lines without significantly affecting their viability, suggesting that although the cells had ceased to divide, they were not yet undergoing apoptosis. Cell cycle analysis using the cell-permeant dye, propidium iodide, indicated that NaBu significantly blocked the cell cycle progression of HMC-1.1 and HMC-1.2 from G1 to G2/M phases. Furthermore, NaBu downregulated the expression of C-KIT mRNA and KIT protein expression in all three cell lines, but this effect was most significant in the HMC-1.1 and HMC-1.2, both of which harbour activating mutations in KIT, which proliferate more rapidly than LAD2. These data support earlier observations showing that human mast cell lines are sensitive to histone deacetylase inhibition. However, our data presents the novel observation that inhibition of cell proliferation by NaBu was not associated with a loss in cell viability but rather an arrest of the cell cycle. Higher concentrations of NaBu led to modest increases in histamine content, tryptase expression, and granularity. In conclusion, NaBu treatment of human mast cell lines led to a modest enhancement of the hallmarks of mature mast cells.

Epigenetic histone modification by butyrate downregulates KIT and attenuates mast cell function

“… 5 Recently, using malignant MC lines, butyrate at much lower concentrations (0.01–1 mM) was reported to suppress MC proliferation and promote differentiation via suppressing KIT. 36 The discrepancy could be due to the differences in the MCs used (malignant MC lines vs. primary BMMCs) in both of the studies. SCFA relay their signals via cell surface G‐protein‐coupled receptors GPR41, GPR43 and GPR109a, or by acting as a HDAC inhibitor in immune cells to modulate gene expression in cell proliferation and differentiation.…”

“…Both p38 and Erk were implicated in SCF‐mediated MC survival and proliferation 5 . Recently, using malignant MC lines, butyrate at much lower concentrations (0.01–1 mM) was reported to suppress MC proliferation and promote differentiation via suppressing KIT 36 . The discrepancy could be due to the differences in the MCs used (malignant MC lines vs. primary BMMCs) in both of the studies.…”

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…The pathways mentioned above influence cell survival, proliferation, and the circumvention of apoptosis, all of which are vital facets of tumor progression. The enduring immunological responses and inflammatory mediators can promote oxidative stress and DNA damage, intensifying carcinogenic potential[ 111 , 112 ]. In addition, Chekol et al [ 113 ] have highlighted that the inflammatory response can lead to the production of immunomodulatory substances, including Tregs and anti-inflammatory cytokines.…”

Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment

“…The stages of maturation are presented according to Mendoza et al, 2021 [29]. Images of mature mast cells using electron microscopy are shown in the paper by MacDonald et al [30]. Five types of morphologically distinct granules were identified in the cytoplasm of MCs: (type I) electron-dense core surrounded by sparse particulates; (type II) less electron-dense and more electron-lucent core; (type III) uniform lumen/particulates; (type IV) a mixture of electron-dense vesicles; and (type V) particulates and scroll-like or multi-lamellar vesicles [30].…”