RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Mutations in chromatin regulators are key drivers in cancer.
• DNA hypomethylating agents like 5-aza-2 -deoxycytidine (DAC) disrupt cancer epigenomic stability.
• SETD2 mutations are prevalent in advanced kidney cancers.

Purpose of the Study:

• To investigate the therapeutic potential of DAC in SETD2-mutant kidney cancers.
• To elucidate the molecular mechanisms underlying DAC sensitivity in this context.
• To explore the synergy of DAC with immunotherapy.

Main Methods:

• In vitro and in vivo drug sensitivity assays.
• Epigenomic profiling (DNA methylation, histone modifications).
• Transcriptomic analysis (RNA sequencing) to identify splicing events.

Main Results:

• SETD2-mutant kidney cancer cells exhibit heightened sensitivity to DAC.
• DAC treatment induces mis-splicing events, including exon inclusions/extensions, in SETD2-loss contexts.
• H3K9me3 deposition at intronic transposable elements, not DNA methylation changes, correlates with increased mis-splicing.
• DAC exacerbates mis-splicing and viral mimicry responses in SETD2-deficient cells.

Conclusions:

• SETD2 deficiency predisposes kidney cancers to DAC-induced mis-splicing.
• DAC therapy can be a targeted treatment for SETD2-mutant kidney cancers.
• The combination of DAC with immunotherapy holds promise for enhanced therapeutic outcomes.