Deciphering the interplay between SETD2 mediated H3K36me3 and RNA N6-methyladenosine in clear cell renal cell...

Area of Science:

• Epigenetics and RNA biology
• Cancer molecular mechanisms
• Renal cell carcinoma research

Background:

• Clear cell renal cell carcinoma (ccRCC) frequently involves VHL loss and mutations in epigenetic regulators like SETD2.
• SETD2 mutations are linked to poor prognosis, metastasis, and altered cell metabolism.
• The interplay between RNA m6A modification and H3K36me3, regulated by SETD2, is unexplored in ccRCC.

Purpose of the Study:

• To investigate the relationship between SETD2, H3K36me3, and m6A modification in ccRCC.
• To identify how SETD2 loss affects m6A distribution and gene expression, particularly in metabolic pathways.
• To explore therapeutic strategies targeting m6A in SETD2-mutant ccRCC.

Main Methods:

• Utilized SETD2 isogenic knockout and rescue ccRCC cell line models.
• Analyzed m6A redistribution and transcriptome changes upon SETD2 depletion.
• Assessed histone modification patterns, including active enhancers, using a panel of six modifications.
• Investigated the effect of METTL3 inhibition or ablation in SETD2-deficient cells.

Main Results:

• SETD2 depletion caused significant m6A redistribution in the ccRCC transcriptome, affecting metabolic reprogramming genes.
• m6A modification shifted to regions with gained active enhancers following SETD2 inactivation.
• Pharmacologic or genetic targeting of METTL3 reversed SETD2 loss-associated metabolic reprogramming and reduced cell viability in SETD2-deficient ccRCC cells.

Conclusions:

• SETD2 loss dynamically alters m6A patterns in ccRCC, influencing metabolic pathways.
• The m6A-H3K36me3 interplay represents a potential therapeutic vulnerability in SETD2-mutant ccRCC.
• Targeting m6A, specifically METTL3, shows promise as a novel therapeutic approach for this ccRCC subtype.