Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism

Abstract

Kr-POK (ZBTB7c) is a kidney cancer-related POK transcription factor that not only represses transcription of CDKN1A but also increases expression of FASN. However, precisely how Kr-POK affects cell metabolism by controlling gene expression in response to an energy source in rapidly proliferating cells remains unknown. In this study, we characterized the molecular and functional features of Kr-POK in the context of tumor growth and glutamine metabolism. We found that cells expressing Kr-POK shRNA exhibited more severe cell death than control cells in glucose-deprived medium, and that knockdown of Kr-POK decreased glutamine uptake. Glutamine is critical for tumor cell proliferation. Glutaminase (GLS1), which is activated by p-STAT1, catalyzes the initial reaction in the pathway of glutaminolysis. Kr-POK interacts with PIAS1 to disrupt the interaction between PIAS1 and p-STAT1, and free p-STAT1 can activate GLS1 transcription through an interaction with p300. Kr-POK can be also sumoylated by PIAS1, facilitating Kr-POK degradation by the ubiquitin-mediated proteasomal pathway. Finally, we showed that repression of Kr-POK inhibited tumor growth in vivo in a xenograft model by repressing GLS1 expression. Taken together, our data reveal that Kr-POK activates GLS1 transcription and increases glutamine uptake to support rapid cancer cell proliferation.