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POU2AF2/C11orf53 functions as a co-activator of POU2F3 by maintaining chromatin accessibility and enhancer activity

ABSTRACT: Small cell lung cancer (SCLC), accounting for around 15% of all lung cancers, often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. The POU class 2 homeobox 3 (POU2F3) is a master regulator of tuft cell identity and defines a subtype of SCLC tumors (SCLC-P subtype) that lack the expression of neuroendocrine markers. Here, we have identified a previously uncharacterized protein C11orf53, which is co-expressed with POU2F3 in both SCLC cell lines and patient samples, and defines the same SCLC subtype. C11orf53 is an essential gene for SCLC-P subtype cells’ survival based on genome wide CRISPR screen, and genetic depletion of C11orf53 or POU2F3 induces apoptosis in different SCLC-P subtype cell lines. Furthermore, our biochemical and genome-wide studies have demonstrated that C11orf53 is a novel chromatin-bound protein that occupies broad active enhancer domains and regulates gene expression at active enhancers. Mechanistically, C11orf53 directly interacts with POU2F3 at the POUs domain, and is recruited to chromatin by POU2F3. Depletion of C11orf53 dramatically reduced enhancer H3K27ac levels and chromatin accessibility, resulting a reduction of the expression of POU2F3-dependent tuft cell markers. Based on the expression pattern and molecular function, we have renamed C11orf53 as "POU Class 2 Homeobox Associating Factor 2" (POU2AF2). In summary, our study has identified a new co-activator of POU2 family transcription factors, and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197426 | GEO | 2022/09/28

REPOSITORIES: GEO

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