Tumorigenic mechanism of renal clear cell carcinoma: deletion of the KDM5C gene causes glycogen metabolism to recompose and inhibit iron death

In order to clarify the connection between VHL and KDM5C in glycogen accumulation, the authors also conducted knockout experiments on Caki-1 cells and found that either deletion of VHL and KDM5C would lead to glycogen accumulation, and there was an additive effect on knockout of both, indicating that KDM5C may have the ability to

Figure 3.

KDM5C histone demethylase activity is necessary for its role in regulating gene expression involvedin glycogenesis, glycogenolysis, and PPP To explore the mechanism of action of KDM5C in glycogen metabolism, the authors transcribed and sequenced

Figure 4.

KDM5C inhibits the flowof glucose to PPP Although the above results show that KDM5C can regulate glycogen metabolism and PPP at the same time, the direction of its specific regulation is still unclear

Figure 5.

KDM5C inhibits tumorigenicPPP mainly by promoting iron death in terms of anti-ROS activity and tumor invasion, of which the interproduct NADPH is an indicator

Figure 6.

KDM5C knockout confers resistance to ROS and iron death on cancer cells After

Figure 7.

Cancer-associated KDM5C mutations are deficientin inhibiting glycogen accumulation and promoting iron death Sequencing identification to the enrichment of most mutations in the JmjN and JmjC domains (Figure 8 A), in order to assess the effects of these cancer-associated KDM5C mutations on glycogen accumulation and iron death, several JmjN and JmjC domain-associated missense mutations were selected and corresponding RCC4 cell lines for stable expression of mutant proteins were constructed (Figure 8).
A）
。 Interestingly, all of these mutants behave like H514A and are not effective in lowering glycogen and G6P levels (Figure 8B), and none of them sensitize cells to iron death or ROS inducers (Figure 8C
).

Figure 8.
Clinically associated KDM5C mutants fail to reduce glycogen levels and inhibit iron death

Based on the previous results, the authors of BioFun discovery proposed a model of inactivated KDM5C mutations in ccRCC
.
As shown in Figure 9, female KDM5C has two active alleles; Therefore, after a single gene is altered, the female does not completely lose her gene
.
In contrast, in men, a kidney cell mutation inactivates the only allele of the KDM5C gene, potentially promoting tumorigenesis
by increasing glycogen production/glycogen breakdown and inhibiting iron death.
Therefore, men are more likely to develop ccRCC
.

 

Figure 9.
Inactivated KDM5C mutation and ccRCC pathogenesis model

Conclusion
The paper reveals that the histone-modified gene KDM5C inactivation mutation reprograms glycogen metabolism and subsequent PPP and induces iron death resistance, thereby expanding the KDM5C functional library, which is critical for tumorigenesis in ccRCC and helps explain the long-term dilemma
of male dominance in human cancers.
In addition, the findings may indicate therapeutic value
in targeting glycogen metabolism in ccRCC.

Text/A-Fun Metabolomics