Translocalization of enhanced PKM2 protein into the nucleus induced by cancer upregulated gene 2 confers cancer stem cell-like phenotypes

다국어 초록 (Multilingual Abstract)

Increased mRNA levels of cancer upregulated gene (CUG)2 havebeen detected in many different tumor tissues using Affymetrixmicroarray. Oncogenic capability of the CUG2 gene has beenfurther reported. However, the mechanism by which CUG2overexpression promotes cancer stem cell (CSC)-like phenotypesremains unknown. With recent studies showing that pyruvatekinase muscle 2 (PKM2) is overexpressed in clinical tissues fromgastric, lung, and cervical cancer patients, we hypothesized thatPKM2 might play an important role in CSC-like phenotypes causedby CUG2 overexpression. The present study revealed that PKM2protein levels and translocation of PKM2 into the nucleus wereenhanced in CUG2-overexpressing lung carcinoma A549 andimmortalized bronchial BEAS-2B cells than in control cells. Expressionlevels of c-Myc, CyclinD1, and PKM2 were increasedin CUG2-overexpressing cells than in control cells. Furthermore,EGFR and ERK inhibitors as well as suppression of Yap1 andNEK2 expression reduced PKM2 protein levels. Interestingly,knockdown of β-catenin expression failed to reduce PKM2 proteinlevels. Furthermore, reduction of PKM2 expression with itssiRNA hindered CSC-like phenotypes such as faster wound healing,aggressive transwell migration, and increased size/numberof sphere formation. The introduction of mutant S37A PKM2-greenfluorescence protein (GFP) into cells without ability to move tothe nucleus did not confer CSC-like phenotypes, whereas forcedexpression of wild-type PKM2 promoted such phenotypes. Overall,CUG2-induced increase in the expression of nuclear PKM2contributes to CSC-like phenotypes by upregulating c-Myc andCyclinD1 as a co-activator.

참고문헌 (Reference)

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