Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism
Man-Wook Hur1, Jae-Hyeon Yoon1, Min-Young Kim1
1Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-ro, SeoDaeMoon-ku, Seoul 03722, Republic of Korea.
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.
Insights
Kr-POK transcription factor promotes cancer cell growth by increasing glutamine uptake. Inhibiting Kr-POK reduces tumor growth by repressing glutaminase (GLS1) expression.
Area of Science:
- Molecular Biology
- Cancer Research
- Metabolic Pathways
Background:
- Kr-POK (ZBTB7c) is a kidney cancer-associated transcription factor influencing CDKN1A and FASN expression.
- The role of Kr-POK in regulating cell metabolism, particularly glutamine metabolism in proliferating cells, is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which Kr-POK affects tumor growth and glutamine metabolism.
- To elucidate Kr-POK's role in regulating glutaminase (GLS1) expression and its impact on cancer cell proliferation.
Main Methods:
- Kr-POK knockdown using shRNA to assess effects on cell viability and glutamine uptake under glucose deprivation.
- Co-immunoprecipitation assays to study protein-protein interactions (Kr-POK, PIAS1, p-STAT1, p300).
- In vivo xenograft model to evaluate the effect of Kr-POK repression on tumor growth.
Main Results:
- Kr-POK knockdown led to increased cell death in glucose-deprived conditions and reduced glutamine uptake.
- Kr-POK interacts with PIAS1 to inhibit p-STAT1 binding to PIAS1, thereby freeing p-STAT1 to activate GLS1 transcription via p300.
- Kr-POK sumoylation by PIAS1 targets it for proteasomal degradation.
- Repression of Kr-POK significantly inhibited tumor growth in vivo by downregulating GLS1 expression.
Conclusions:
- Kr-POK promotes cancer cell proliferation by activating GLS1 transcription and enhancing glutamine uptake.
- Targeting Kr-POK represents a potential therapeutic strategy for inhibiting tumor growth by disrupting glutamine metabolism.
Related Concept Videos
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Abnormal Proliferation
Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
The Ras Gene
Ras is a...
Negative Regulator Molecules
PI3K/mTOR/AKT Signaling Pathway


