PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation-dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.

Automated summary

Lipid deposition plays important roles in the development, metastasis, and drug resistance of clear cell renal cell carcinoma (ccRCC), and the molecular mechanisms underlying this deposition remain largely unknown. Through a CRISPR-Cas9 screening, the epigenetic regulator PHF8 was identified as an important regulator in ccRCC lipid deposition. PHF8 is regulated by the VHL/HIF axis and is essential for VHL deficiency-induced lipid deposition. It transcriptionally up-regulates GLUL, which promotes lipid deposition and ccRCC progression. The PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.