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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Translocalization of enhanced PKM2 protein into the nucleus induced by cancer upregulated gene 2 confers cancer stem cell-like phenotypes

  • Yawut, Natpaphan (BK21 plus, Department of Cogno-Mechatronics Engineering, Optomechatronics Research Center) ;
  • Kaowinn, Sirichat (Department of General Science and Liberal Arts, King Mongkut's Institute of Technology, Ladkrabang Prince of Chumphon Campus) ;
  • Cho, Il-Rae (BK21 plus, Department of Cogno-Mechatronics Engineering, Optomechatronics Research Center) ;
  • Budluang, Phatcharaporn (BK21 plus, Department of Cogno-Mechatronics Engineering, Optomechatronics Research Center) ;
  • Kim, Seonghye (BK21 plus, Department of Chemistry, Pusan National University) ;
  • Kim, Suhkmann (BK21 plus, Department of Chemistry, Pusan National University) ;
  • Youn, So Eun (Department of Biomedical Sciences, Dong-A University) ;
  • Koh, Sang Seok (Department of Biomedical Sciences, Dong-A University) ;
  • Chung, Young-Hwa (BK21 plus, Department of Cogno-Mechatronics Engineering, Optomechatronics Research Center)
  • Received : 2021.08.23
  • Accepted : 2021.12.20
  • Published : 2022.02.28
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Abstract

Increased mRNA levels of cancer upregulated gene (CUG)2 have been detected in many different tumor tissues using Affymetrix microarray. Oncogenic capability of the CUG2 gene has been further reported. However, the mechanism by which CUG2 overexpression promotes cancer stem cell (CSC)-like phenotypes remains unknown. With recent studies showing that pyruvate kinase muscle 2 (PKM2) is overexpressed in clinical tissues from gastric, lung, and cervical cancer patients, we hypothesized that PKM2 might play an important role in CSC-like phenotypes caused by CUG2 overexpression. The present study revealed that PKM2 protein levels and translocation of PKM2 into the nucleus were enhanced in CUG2-overexpressing lung carcinoma A549 and immortalized bronchial BEAS-2B cells than in control cells. Expression levels of c-Myc, CyclinD1, and PKM2 were increased in CUG2-overexpressing cells than in control cells. Furthermore, EGFR and ERK inhibitors as well as suppression of Yap1 and NEK2 expression reduced PKM2 protein levels. Interestingly, knockdown of β-catenin expression failed to reduce PKM2 protein levels. Furthermore, reduction of PKM2 expression with its siRNA hindered CSC-like phenotypes such as faster wound healing, aggressive transwell migration, and increased size/number of sphere formation. The introduction of mutant S37A PKM2-green fluorescence protein (GFP) into cells without ability to move to the nucleus did not confer CSC-like phenotypes, whereas forced expression of wild-type PKM2 promoted such phenotypes. Overall, CUG2-induced increase in the expression of nuclear PKM2 contributes to CSC-like phenotypes by upregulating c-Myc and CyclinD1 as a co-activator.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2020R 1F1A 1048183) and the Technology Innovation Program (N0002310 and P0008763) funded by the Ministry of Trade, 511 Industry, and Energy (MOTIE, Korea). This work was also supported by Korea Institute for Advancement of Technology (KIAT) grant funded by the Korea Government (MOTIE) (P0008763, The Competency Development Program for Industry Specialist).

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