Ginsenoside Rh2 reduces m6A RNA methylation in cancer via the KIF26B-SRF positive feedback loop

Abstract

Background The underlying mechanisms of the potential tumor-suppressive effects of ginsenoside Rh2 are complex. N 6-methyladenosine (m6A) RNA methylation is usually dysregulated in cancer. This study explored the regulatory effect of ginsenoside Rh2 on m6A RNA methylation in cancer. Methods: m6A RNA quantification and gene-specific m6A RIP-qPCR assays were applied to assess total and gene-specific m6A RNA levels. Co-immunoprecipitation, fractionation western blotting, and immunofluorescence staining were performed to detect protein interactions and distribution. QRT-PCR, dual-luciferase, and ChIP-qPCR assays were conducted to check the transcriptional regulation. Results Ginsenoside Rh2 reduces m6A RNA methylation and KIF26B expression in a dose-dependent manner in some cancers. KIF26B interacts with ZC3H13 and CBLL1 in the cytoplasm of cancer cells and enhances their nuclear distribution. KIF26B inhibition reduces m6A RNA methylation level in cancer cells. SRF bound to the KIF26B promoter and activated its transcription. SRF mRNA m6A abundance significantly decreased upon KIF26B silencing. SRF knockdown suppressed cancer cell proliferation and growth both in vitro and in vivo , the effect of which was partly rescued by KIF26B overexpression. Conclusion: ginsenoside Rh2 reduces m6A RNA methylation via downregulating KIF26B expression in some cancer cells. KIF26B elevates m6A RNA methylation via enhancing ZC3H13/CBLL1 nuclear localization. KIF26B-SRF forms a positive feedback loop facilitating tumor growth.

Comparison between the Biological Active Compounds in Plants with Adaptogenic Properties (Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus and Panax ginseng)

“…According to data obtained from animal studies, ginsenosides have great potential to be used for the treatment of cardiovascular diseases, hepatic disorders and obesity [ 227 , 228 , 229 , 230 , 231 , 232 , 233 ]. According to data obtained from cell culture studies, ginsenosides have great potential to be used for the treatment cardiovascular diseases, hypercholesterolemia, and some types of cancer [ 234 , 235 , 236 , 237 ].…”

Updating the therapeutic role of ginsenosides in breast cancer: a bibliometrics study to an in-depth review

“…Notably, methylation stands as a pivotal factor in tumorigenesis and progression ( Pouliot et al, 2015 ). Ginsenoside Rh2 was reported to reduce m6A RNA methylation by downregulating KIF26B expression in breast cancer cells ( Hu et al, 2021 ). In another study, ginsenoside Rh2 induced hypomethylation of an entire chromosomal element LINE1.…”

Ginsenosides: changing the basic hallmarks of cancer cells to achieve the purpose of treating breast cancer

“…For example, they can modulate the expression of genes such as BBX, TNFAIP3, and SLC1A1 through non-coding RNAs like lnc STXBP5-AS1, lnc RFX3-AS1, miR-3614-3p, and others, thereby exerting anti-tumor activity. Additionally, Rg3 [ 117 ] and Rh2 [ 118 , 119 ] have been shown to regulate the methylation levels and demethylation levels of breast cancer-related genes and proteins, including TRMT1l, KDM5A, and CAS1, through mechanisms such as N6-adenylate methylation, thus altering the breast cancer-associated microenvironment, enhancing immunogenicity, and inhibiting cancer cell growth. Furthermore, Rg1 [ 120 ] has been demonstrated to inhibit the phosphorylation of histone H3Thr3 mediated by Haspin kinase, leading to an increase in the width of the metaphase plate and spindle instability during cancer cell division, resulting in a delay in the progression of mitotic differentiation and inhibition of proliferation in breast cancer cells.…”