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Updated: Jul 10, 2025
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Oncogenic Cells of Renal Embryonic Lineage Sensitive to the Small-Molecule Inhibitor QC6352 Display Depletion of KDM4
Prahalathan Pichavaram1, Carolyn M Jablonowski1, Jie Fang1
1Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee.
Abstract:
The histone lysine demethylases KDM4A-C are involved in physiologic processes including stem cell identity and self-renewal during development, DNA damage repair, and cell-cycle progression. KDM4A-C are overexpressed and associated with malignant cell behavior in multiple human cancers and are therefore potential therapeutic targets. Given the role of KDM4A-C in development and cancer, we aimed to test the potent, selective KDM4A-C inhibitor QC6352 on oncogenic cells of renal embryonic lineage. The anaplastic Wilms tumor cell line WiT49 and the tumor-forming human embryonic kidney cell line HEK293 demonstrated low nanomolar QC6352 sensitivity. The cytostatic response to QC6352 in WiT49 and HEK293 cells was marked by induction of DNA damage, a DNA repair-associated protein checkpoint response, S-phase cell-cycle arrest, profound reduction of ribosomal protein gene and rRNA transcription, and blockade of newly synthesized proteins. QC6352 caused reduction of KDM4A-C levels by a proteasome-associated mechanism. The cellular phenotype caused by QC6352 treatment of reduced migration, proliferation, tumor spheroid growth, DNA damage, and S-phase cell-cycle arrest was most closely mirrored by knockdown of KDM4A as determined by siRNA knockdown of KDM4A-C. QC6352 sensitivity correlated with high basal levels of ribosomal gene transcription in more than 900 human cancer cell lines. Targeting KDM4A may be of future therapeutic interest in oncogenic cells of embryonic renal lineage or cells with high basal expression of ribosomal protein genes.
Insights
The KDM4A-C inhibitor QC6352 effectively targets renal embryonic lineage cancer cells by inducing DNA damage and cell-cycle arrest. This suggests KDM4A inhibition is a promising therapeutic strategy for specific cancers.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Histone lysine demethylases KDM4A-C regulate crucial cellular processes like stem cell renewal and DNA repair.
- KDM4A-C overexpression is linked to aggressive behavior in various human cancers, identifying them as potential therapeutic targets.
Purpose of the Study:
- To evaluate the efficacy of the selective KDM4A-C inhibitor QC6352 against oncogenic cells derived from the renal embryonic lineage.
- To investigate the molecular mechanisms underlying QC6352's anti-cancer effects.
Main Methods:
- Treatment of anaplastic Wilms tumor (WiT49) and human embryonic kidney (HEK293) cell lines with QC6352.
- Assessment of cellular responses including DNA damage, cell-cycle progression, gene transcription, and protein synthesis.
- siRNA-mediated knockdown of KDM4A-C to compare phenotypic effects.
- Analysis of QC6352 sensitivity across over 900 human cancer cell lines.
Main Results:
- WiT49 and HEK293 cells exhibited high sensitivity to QC6352, with low nanomolar responses.
- QC6352 induced DNA damage, S-phase arrest, reduced ribosomal gene transcription, and inhibited protein synthesis.
- QC6352 treatment led to proteasomal degradation of KDM4A-C.
- Phenotypic changes mirrored KDM4A knockdown, and sensitivity correlated with high ribosomal gene transcription.
Conclusions:
- QC6352 demonstrates potent anti-cancer activity in renal embryonic lineage cells by targeting KDM4A-C.
- The drug's mechanism involves DNA damage, cell-cycle arrest, and suppression of ribosomal biogenesis.
- Targeting KDM4A represents a potential therapeutic avenue for cancers with high ribosomal gene expression.
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