Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. (1st November 2021)

• Record Type: Journal Article
• Authors: Yusenko, Maria V.; Biyanee, Abhiruchi; Andersson, Mattias K.; Radetzki, Silke; von Kries, Jens P.; Stenman, Göran; Klempnauer, Karl-Heinz
• Is Part Of: Cancer letters. Volume 520(2021)
• Page Start: 132
• Page End: 142
• Publication Date: 2021-11-01
• Subjects: MYB -- Inhibitor -- Myeloid leukemia -- Adenoid cystic carcinoma -- Proteasome inhibitor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.07.010
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies. Here, we have used a MYB reporter cell line to screen a library of FDA-approved drugs for novel MYB inhibitors. We demonstrate that proteasome inhibitors have significant MYB-inhibitory activity, prompting us to characterize the proteasome inhibitor oprozomib in more detail. Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition. Highlights: Proteasome inhibitor oprozomib and related compounds are potent MYB-inhibitory agents. Oprozomib induces differentiation and cell death in acute myeloid leukemia (AML) cells. Oprozomib inhibits viability MYB/NFIB positive adenoid cystic carcinoma (ACC) cells. Oprozomib inhibits MYB activity via co-activator p300.