The NEXT complex regulates H3K27me3 levels to affect cancer progression by degrading G4/U-rich lncRNAs

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Research

Background:

• Polycomb repressive complex 2 (PRC2) deposits H3K27me3, crucial for gene silencing in development and cancer.
• The nuclear exosome targeting (NEXT) complex degrades noncoding RNAs in the nucleoplasm.

Purpose of the Study:

• To investigate the functional relationship between the NEXT complex and H3K27me3 levels.
• To elucidate the role of ZCCHC8 and specific lncRNAs in this regulatory pathway.

Main Methods:

• ZCCHC8 depletion experiments to observe lncRNA and H3K27me3 changes.
• Analysis of G-quadruplex (G4) and U-Rich motifs in lncRNAs.
• Investigation of EZH2 binding and PRC2 recruitment dynamics.
• Correlation analysis in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patient tissues.
• Assessment of EZH2 inhibitor sensitivity.

Main Results:

• NEXT complex deficiency leads to decreased H3K27me3 levels.
• ZCCHC8 depletion upregulates nascent G4/U-Rich lncRNAs.
• G4 motifs bind EZH2, hindering PRC2 chromatin recruitment; U-Rich motifs target lncRNAs for NEXT complex degradation.
• High ZCCHC8 expression in ccRCC and LUAD correlates with excessive lncRNA degradation, PRC2 release, and increased H3K27me3 at adjacent loci.
• Tumor suppressor genes like SEMA5A and ARID1A are downregulated.
• Cells with higher ZCCHC8 expression show increased sensitivity to the EZH2 inhibitor Tazemetostat.

Conclusions:

• The NEXT complex regulates H3K27me3 levels through the degradation of nascent G4/U-Rich lncRNAs.
• This mechanism plays a significant role in cancer, affecting gene silencing and offering potential therapeutic targets.