Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rh2 reduces m6A RNA methylation in cancer via the KIF26B-SRF positive feedback loop

  • Hu, Chunmei (Department of Otolaryngology-Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China) ;
  • Yang, Linhan (Outpatient Department, Chengdu Aurora Huan Hua Xiang) ;
  • Wang, Yi (Department of Specialty of Geriatric Endocrinology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China) ;
  • Zhou, Shijie (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center) ;
  • Luo, Jing (Department of Breast Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China) ;
  • Gu, Yi (Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China)
  • Received : 2021.03.24
  • Accepted : 2021.05.12
  • Published : 2021.11.15
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Abstract

Background: The underlying mechanisms of the potential tumor-suppressive effects of ginsenoside Rh2 are complex. N6-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.

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References

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