LAUSR

Hypoxia increases methylated histones by inhibiting O2- and α-ketoglutarate-dependent histone lysine demethylases (KDMs). This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). Raf-activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated clipping of histone H3, H2B and H4. Hypoxia protects histones from CTSL by increasing histone methylation without reducing the amount and activity of CTSL. Forced enhancement of methylated histones protected histones from clipping during OIS, even under normoxia, but failed to block SAHFs. Altogether, these results suggest that maintenance of methylated histones is sufficient to protect histones from CTSL, not sufficient but necessary for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other mechanisms to inhibit SAHFs. Hypoxia protects histones and chromatin from dramatic epigenetic changes by increasing methylated histones. Citation Format: Hyunsung Park, Soojeong Chang. Hypoxia increases the methylated histones to prevent histone clipping during Raf-induced senescence. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4766.