Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Cells

Hiroya Kondo¹  Kenji Mishiro¹  Kazuma Ogawa¹  Masaharu Hazawa¹  Richard W. Wong¹  Toshinari Minamoto²  Takahiro Domoto²  Munetaka Kunishima³  Akiko Kobayashi⁴  Yuki Iwashima⁵  Keesiang Lim⁶  Yujia Qiu⁶ 

[1] Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-0934, Japan;Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;Laboratory of Molecular Cell Biology, School of Natural System, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;WPI-Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;

关键词: CRC;    BRD4;    NPC;    NUP210;    nuclear size;    aminocyclopropenone;   

DOI  :  10.3390/cells11030317

来源: DOAJ

【 摘 要 】

Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

【 授权许可】

Unknown