Abstract
Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. We recently identified the YEATS domain as a novel acetyllysine-binding module; however, the functional importance of YEATS domain-containing proteins in human cancer remains largely unknown. Here, we show that the YEATS2 gene is highly amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell growth and survival. YEATS2 binds to acetylated histone H3 via its YEATS domain. The YEATS2-containing ATAC complex co-localizes with H3K27 acetylation (H3K27ac) on the promoters of actively transcribed genes. Depletion of YEATS2 or disruption of the interaction between its YEATS domain and acetylated histones reduces the ATAC complex-dependent promoter H3K9ac levels and deactivates the expression of essential genes. Taken together, our study identifies YEATS2 as a histone H3K27ac reader that regulates a transcriptional program essential for NSCLC tumorigenesis.
Highlights
Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development
YEATS domain-containing 2 (YEATS2) is a stoichiometric component of the ATAC histone acetyltransferases (HATs) complex, which catalyzes histone acetylation, mainly on H3K9 and H3K14, by the enzymatic subunit GCN5 or PACF12, 13
Compared with the immortalized normal cells, we observed elevated levels of GCN5 and PCAF in most examined lung cancer cells (Fig. 1b), suggesting that essential subunits of the ATAC complex cooperate in human cancers likely leading to an super-active complex
Summary
Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. We recently identified the YEATS domain as a novel acetyllysine-binding module; the functional importance of YEATS domain-containing proteins in human cancer remains largely unknown. Depletion of YEATS2 or disruption of the interaction between its YEATS domain and acetylated histones reduces the ATAC complex-dependent promoter H3K9ac levels and deactivates the expression of essential genes. Genes and Development and Epigenetics & Molecular Carcinogenesis Graduate Programs, The University of Texas Graduate School of Biomedical Sciences, Houston, Lysine acetylation is one of the most frequent posttranslational modifications occurring on histones that play a critical role in regulating chromatin dynamics and the accessibility of the underlying DNA in eukaryotes[1]. Disruption of acetylation recognition of YEATS2-abrogated GCN5/PCAF-mediated promoter histone acetylation and suppressed the expression of its target genes, including the ribosomal protein-encoding genes that are essential for cell growth and survival. Our results identified YEATS2 as a histone H3K27ac reader that epigenetically regulates a transcriptional program essential for NSCLC tumorigenesis
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