MTH1 suppression enhances the stemness of MCF7 through upregulation of STAT3

  • Free Radic Biol Med. 2022 Aug 1:188:447-458. doi: 10.1016/j.freeradbiomed.2022.06.240.
Jin Li  1 ,  Zi-Hui Wang  2 ,  Ya-Min Dang  2 ,  Dan-Ni Li  3 ,  Zhen Liu  2 ,  Da-Peng Dai  1 ,  Jian-Ping Cai  4
Affiliations
  • 1. The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
  • 2. The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China.
  • 3. The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, PR China.
  • 4. The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China. Electronic address: [email protected].
PMID: 35809767 DOI: 10.1016/j.freeradbiomed.2022.06.240
Abstract

MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast Cancer stemness has not been reported yet. Here, we constructed breast Cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44+CD24-/low subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT-qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2, Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1-knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast Cancer Stem Cells (BCSCs) and promoted stemness properties in MCF7 cells.

Keywords
BCSCs; MCF7; MTH1; STAT3; Stemness.
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