Zheng Bin, Iwanaszko Marta, Soliman Shimaa Hassan AbdelAziz, Ishi Yukitomo, Gold Sarah, Qiu Ruxuan, Howard Benjamin Charles, Das Madhurima, Zhao Zibo, Hashizume Rintaro, Wang Lu, Shilatifard Ali
Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sci Adv. 2025 Mar 14;11(11):eads4200. doi: 10.1126/sciadv.ads4200.
The testis-specific BET protein BRDT structurally resembles the ubiquitous BRD4 and is misexpressed in cancer, and we show that BRDT misexpression may affect lung cancer progression. BRDT knockdown in lung cancer cells slowed tumor growth and prolonged survival in a xenograft model. Comparative characterization of PTEFb complex participation and chromatin binding indicates BRD4-redundant and BRD4-distinct BRDT functions. Unlike dual depletion, individual BRD4 or BRDT knockdown did not impair transcriptional responses to hypoxia in BRDT-expressing cells, consistent with redundant function. However, BRD4 depletion/BRDT complementation revealed that BRDT can also release paused RNA polymerase II independently of its bromodomains as we previously demonstrated not to be required for Pol II pause/release function of BRD4, underscoring the functional importance of the C-terminal domains in both BRD4 and BRDT and their potential as therapeutic targets in solid tumors. Based on this study, future investigations should explore BRD4-distinct BRDT functions and BRDT misexpression driving cancer pathogenesis.
睾丸特异性BET蛋白BRDT在结构上与普遍存在的BRD4相似，且在癌症中表达异常，我们发现BRDT表达异常可能影响肺癌进展。在异种移植模型中，肺癌细胞中的BRDT敲低减缓了肿瘤生长并延长了生存期。对PTEFb复合物参与情况和染色质结合的比较表征表明，BRDT具有与BRD4冗余及不同的功能。与双重敲低不同，单独敲低BRD4或BRDT并不损害BRDT表达细胞中对缺氧的转录反应，这与它们的冗余功能一致。然而，BRD4敲低/BRDT互补表明，BRDT也可以独立于其溴结构域释放暂停的RNA聚合酶II，正如我们之前所证明的，这并非BRD4的Pol II暂停/释放功能所必需，这突出了BRD4和BRDT中C末端结构域的功能重要性及其作为实体瘤治疗靶点的潜力。基于这项研究，未来的研究应探索BRDT与BRD4不同的功能以及BRDT表达异常驱动癌症发病机制的情况。
