Abstract
Small cell lung cancer (SCLC), accounting for around 13% 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 the SCLC-P subtype that lacks the neuroendocrine markers. Here, we have identified a previously uncharacterized protein, C11orf53, which is coexpressed with POU2F3 in both SCLC cell lines and patient samples. Mechanistically, C11orf53 directly interacts with POU2F3 and is recruited to chromatin by POU2F3. Depletion of C11orf53 reduced enhancer H3K27ac levels and chromatin accessibility, resulting in a reduction of POU2F3-dependent gene expression. On the basis of the molecular function of C11orf53, we renamed it as “POU Class 2 Homeobox Associating Factor 2” (POU2AF2). In summary, our study has identified a new coactivator of POU2F3 and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.
| Original language | English (US) |
|---|---|
| Article number | eabq2403 |
| Journal | Science Advances |
| Volume | 8 |
| Issue number | 40 |
| DOIs | |
| State | Published - Oct 2022 |
Funding
Acknowledgments: We would like to thank B. Braschi and HUGO Gene Nomenclature Committee (HGNC) for working with us to rename C11orf53 gene as POU2AF2 officially. We would like to thank Y. Shi and C. Vakoc for critical discussion. We would like to thank F. Zhang for the gifts of the Px330 and lentiCRISPR v2 vectors. Funding: L.W. was supported by NIH grant R35GM146979 and the Research Scholar Grant (RSG-22-039-01-DMC) from the American Cancer Society. L.W. was also supported by Lynn Sage Scholar Award. R.H. was supported by the U.S. National Institutes of Health (R01NS126513). Author contributions: L.W. and Z.Z. designed the study. A.P.S., N.T., and L.W. performed all the biochemistry and sequencing experiments. N.T. performed the animal experiments. Z.Z. performed the bioinformatics analysis. A.P.S., N.T., and L.W. wrote the manuscript. N.T., A.P.S., J.W., R.H., and L.W. revised the manuscript. All authors read and approved the final manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: NGS data generated for this study are available at the Gene Expression Omnibus (GEO) under accession number GSE197426. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General
