Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness...

Area of Science:

• Epigenetics
• Cancer Biology
• Genomics

Background:

• Epigenetic modifiers are frequently altered in human cancers, presenting potential therapeutic targets.
• Chromatin accessibility in cancer cells-of-origin correlates with mutation patterns, but long-term effects of targeting epigenetic modifiers on cancer mutability remain unclear.

Purpose of the Study:

• To investigate the long-term impact of targeting the histone H3 lysine 9 (H3K9) methyltransferase G9a on mutability and tumor progression in a murine cancer model.

Main Methods:

• Increased chromatin accessibility by deleting G9a in murine epidermis.
• Induced squamous tumors using chemical mutagens.
• Analyzed single nucleotide variant burden, global genomic distribution, tumor latency, aggressiveness, cancer progenitor pool, genomic instability, and p53 mutations.

Main Results:

• Deleting G9a did not alter the single nucleotide variant burden or global genomic distribution in chemically induced squamous tumors.
• G9a-depleted tumors exhibited prolonged latency but were more aggressive.
• These tumors showed an expanded cancer progenitor pool, pronounced genomic instability, and frequent loss-of-function p53 mutations.

Conclusions:

• Targeting epigenetic modifiers like G9a may not increase mutability but can promote more aggressive cancer phenotypes.
• Therapeutic strategies inhibiting chromatin modifiers require careful assessment for potential long-term adverse effects, such as promoting aggressive disease and genomic instability.