GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis

  • Oncogenesis. 2022 May 23;11(1):28. doi: 10.1038/s41389-022-00402-w.
Chenggang Zhao  1  2  3  4 ,  Huihan Yu  1  4 ,  Xiaoqing Fan  1  2  3  4  5 ,  Wanxiang Niu  1  2  3  4 ,  Junqi Fan  1  2  3  4 ,  Suling Sun  1  2  3  4 ,  Meiting Gong  1  4 ,  Bing Zhao  6 ,  Zhiyou Fang  7  8  9  10 ,  Xueran Chen  11  12  13  14
Affiliations
  • 1. Anhui Province Key Laboratory of Medical Physics and Technology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China.
  • 2. Science Island Branch, Graduate School of University of Science and Technology of China, No. 96, Jin Zhai Road, 230026, Hefei, Anhui, China.
  • 3. Department of Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China.
  • 4. MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science & Technology of China, No. 96, Jin Zhai Road, 230027, Hefei, Anhui, China.
  • 5. Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), No. 17, Lu Jiang Road, 230001, Hefei, Anhui, China.
  • 6. Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, No. 678, Fu Rong Road, 230601, Hefei, Anhui, China. [email protected].
  • 7. Anhui Province Key Laboratory of Medical Physics and Technology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China. [email protected].
  • 8. Science Island Branch, Graduate School of University of Science and Technology of China, No. 96, Jin Zhai Road, 230026, Hefei, Anhui, China. [email protected].
  • 9. Department of Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China. [email protected].
  • 10. MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science & Technology of China, No. 96, Jin Zhai Road, 230027, Hefei, Anhui, China. [email protected].
  • 11. Anhui Province Key Laboratory of Medical Physics and Technology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China. [email protected].
  • 12. Science Island Branch, Graduate School of University of Science and Technology of China, No. 96, Jin Zhai Road, 230026, Hefei, Anhui, China. [email protected].
  • 13. Department of Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, 230031, Hefei, Anhui, China. [email protected].
  • 14. MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science & Technology of China, No. 96, Jin Zhai Road, 230027, Hefei, Anhui, China. [email protected].
PMID: 35606353 DOI: 10.1038/s41389-022-00402-w
Abstract

Glioblastoma stem cells (GSCs) are a highly tumorigenic cell subgroup of glioblastoma (GBM). Glycogen synthase kinase 3β (GSK3β) is considered a key hub for promoting malignant phenotypes in GBM. However, the functional relationships between GSK3β and GSCs in GBM are unclear. Here, we found that GSK3β was noted as a substrate for ZDHHC4-mediated palmitoylation at the Cys14 residue, which enhanced GBM temozolomide (TMZ) resistance and GSC self-renewal. Clinically, the expression level of ZDHHC4 was upregulated in GBM, which significantly correlated with tumor grade and poor prognosis. The above phenotypes were based on decreasing p-Ser9 and increasing p-Tyr216 by GSK3β palmitoylation, which further activated the enhancer of the zeste homolog 2 (EZH2)-STAT3 pathway. Notably, STAT3 silencing also inhibited ZDHHC4 expression. This study revealed that GSK3β palmitoylation mediated by ZDHHC4 improved the stemness of TMZ-resistant GBM by activating the EZH2-STAT3 signaling axis, providing a new theoretical basis for further understanding the mechanism of TMZ resistance and recurrence after treatment.

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