Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential

Min Zhang; Yang Liu; Lihua Shi; Lei Fang; Liyang Xu; Ying Cao

doi:10.1016/j.jbc.2022.102106

Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential

J Biol Chem. 2022 Jul;298(7):102106. doi: 10.1016/j.jbc.2022.102106. Epub 2022 Jun 4.

Authors

Min Zhang¹, Yang Liu¹, Lihua Shi², Lei Fang³, Liyang Xu², Ying Cao⁴

Affiliations

¹ Shenzhen Research Institute of Nanjing University, Shenzhen, China; MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.
² MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.
³ Jiangsu Key Laboratory of Molecular Medicine of Medical School, Nanjing University, Nanjing, China.
⁴ Shenzhen Research Institute of Nanjing University, Shenzhen, China; MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China. Electronic address: caoying@nju.edu.cn.

Abstract

Neural stemness is suggested to be the ground state of tumorigenicity and pluripotent differentiation potential. However, the relationship between these cell properties is unclear. Here, by disrupting the neural regulatory network in neural stem and cancer cells and by serial transplantation of cancer cells, we show that tumorigenicity and pluripotent differentiation potential are coupled cell properties unified by neural stemness. We show that loss of neural stemness via inhibition of SETDB1, an oncoprotein with enriched expression in embryonic neural cells during vertebrate embryogenesis, led to neuronal differentiation with reduced tumorigenicity and pluripotent differentiation potential in neural stem and cancer cells, whereas enhancement of neural stemness by SETDB1 overexpression caused the opposite effects. SETDB1 maintains a regulatory network comprising proteins involved in developmental programs and basic cellular functional machineries, including epigenetic modifications (EZH2), ribosome biogenesis (RPS3), translation initiation (EIF4G), and spliceosome assembly (SF3B1); all of these proteins are enriched in embryonic neural cells and play active roles in cancers. In addition, SETDB1 represses the transcription of genes promoting differentiation and cell cycle and growth arrest. Serial transplantation of cancer cells showed that neural stemness, tumorigenicity, and pluripotent differentiation potential were simultaneously enhanced; these effects were accompanied by increased expression of proteins involved in developmental programs and basic machineries, including SETDB1 and the abovementioned proteins, as well as by increased alternative splicing events. These results indicate that basic machineries work together to define a highly proliferative state with pluripotent differentiation potential and also suggest that neural stemness unifies tumorigenicity and differentiation potential.

Keywords: SETDB1; alternative splicing; cancer cell; cell differentiation; neural stemness; pluripotency; ribosome; serial transplantation; translation initiation factor; tumorigenicity.

MeSH terms

Carcinogenesis*
Cell Cycle
Cell Differentiation*
Embryonic Development
Flavonoids
Histone-Lysine N-Methyltransferase* / genetics
Histone-Lysine N-Methyltransferase* / metabolism
Neural Stem Cells* / cytology
Pluripotent Stem Cells* / cytology

Substances

3',5,7-trihydoxy-3,4',5'-trimethoxyflavone
Flavonoids
Histone-Lysine N-Methyltransferase
SETDB1 protein, human