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.

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.

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