Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

著者: Artyom A. Alekseyenko, Erica M. Walsh, Barry M. Zee, Tibor Pakozdi, Peter Hsi, Madeleine E. Lemieux, Paola Dal Cin, Tan A. Ince, Peter V. Kharchenko, Mitzi I. Kuroda, Christopher A. French - Proceedings of the National Academy of Sciences, PNAS 2017 被引用: 141

Significance Chromatin factors generally act within large, multisubunit complexes; thus, identifying both their normal and aberrant interactors in cancer should provide important information regarding potential targets for therapeutic intervention. Here, we apply this principle to analysis of BRD4–NUT, a fusion oncoprotein that drives an aggressive subtype of squamous cell cancer. We identify ZNF532 as a prominent BRD4–NUT–interacting protein in an established NUT midline carcinoma patient cell line, and independently discover ZNF532 fused directly to NUT in a newly analyzed patient. Like BRD4–NUT, ZNF532–NUT forms unusually large (100-kb to 1-Mb) domains of hyperactive chromatin, including at the MYC locus, and drives self-reinforcing regulatory loops that are likely to be a powerful strategy for the growth advantage of cancer cells.