A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function

• Published in: The FASEB journal 2015-12, Vol.29 (12), p.4829-4839
• Main Authors: Liu, Yaobin, Huang, Xiangao, He, Xian, Zhou, Yanqing, Jiang, Xiaogang, Chen‐Kiang, Selina, Jaffrey, Samie R., Xu, Guoqiang
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; cullin RING ligase; HEK293 Cells; Humans; Lenalidomide; multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; pomalidomide; Research Communication; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.15-274050

ABSTRACT The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin‐4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48‐linked polyubiquitin chains and that thalidomide blocks the formation of CRBN‐ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin‐4 RING E3 ligase‐mediated degradation of target proteins.—Liu, Y., Huang, X., He, X., Zhou, Y., Jiang, X., Chen‐Kiang, S., Jaffrey, S. R., Xu, G. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. FASEB J. 29, 4829–4839 (2015). www.fasebj.org