Abstract 3232: NOP16 is a histone mimetic that regulates histone H3K27 methylation and gene repression

Abstract Post-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3. NOP16 competitively inhibits the interaction between EED and H3K27me3 and causes EED to translocate from the nucleoplasm to the nucleolus, thereby negatively regulating H3K27me3 modification in the nucleoplasm. NOP16 is overexpressed and linked to poor prognosis in breast cancer. Depletion of NOP16 in breast cancer cell lines causes cell cycle arrest, decreases cell proliferation and selectively decreases expression of E2F target genes and of genes involved in cell cycle, growth and apoptosis. Conversely, ectopic NOP16 expression in triple negative breast cancer cell lines increases cell proliferation, cell migration and invasivity in vitro and tumor growth in vivo, while NOP16 knockout or knockdown has the opposite effect. Thus, NOP16 is a histone mimic that competes with Histone H3 for H3K27 methylation and demethylation. When it is overexpressed in cancer, it derepresses genes that promote cell cycle progression to augment breast cancer growth. Citation Format: Aamir Khan, Ken Takashima, Dian-Jang Lee, María Fernanda Trovero, Xing Wang, M. Hafiz Rothi, Ying Zhang, Zilan Li, Sarah Niesen, Julia Natale, Ernst Schmid, Joseph Al Haddad, Sabine Dietmann, Sumio Ohtsuki, Shannan Ho Sui, Hiroyuki Oshiumi, Judy Lieberman, Eric Lieberman Greer. NOP16 is a histone mimetic that regulates histone H3K27 methylation and gene repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3232.