UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response
Authors
Huiting, L. N.Samaha, Y.
Zhang, G. L.
Roderick, Justine E.
Li, B.
Anderson, N. M.
Wang, Y. W.
Wang, L.
Laroche, F.
Choi, J. W.
Liu, C. T.
Kelliher, Michelle A.
Feng, H.
Document Type
Journal ArticlePublication Date
2018-04-25Keywords
Acute lymphocytic leukaemiaCancer microenvironment
Amino Acids, Peptides, and Proteins
Cancer Biology
Cell Biology
Cellular and Molecular Physiology
Hemic and Lymphatic Diseases
Neoplasms
Therapeutics
Metadata
Show full item recordAbstract
Despite the pivotal role of MYC in tumorigenesis, the mechanisms by which it promotes cancer aggressiveness remain incompletely understood. Here, we show that MYC transcriptionally upregulates the ubiquitin fusion degradation 1 (UFD1) gene in T-cell acute lymphoblastic leukemia (T-ALL). Allelic loss of ufd1 in zebrafish induces tumor cell apoptosis and impairs MYC-driven T-ALL progression but does not affect general health. As the E2 component of an endoplasmic reticulum (ER)-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER. We found that UFD1 inactivation in human T-ALL cells impairs ERAD, exacerbates ER stress, and induces apoptosis. Moreover, we show that UFD1 inactivation promotes the proapoptotic unfolded protein response (UPR) mediated by protein kinase RNA-like ER kinase (PERK). This effect is demonstrated by an upregulation of PERK and its downstream effector C/EBP homologous protein (CHOP), as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor cell apoptosis induced by UFD1 knockdown. Together, our studies identify UFD1 as a critical regulator of the ER stress response and a novel contributor to MYC-mediated leukemia aggressiveness, with implications for targeted therapy in T-ALL and likely other MYC-driven cancers.Source
Leukemia. 2018 Apr 25. doi: 10.1038/s41375-018-0141-x. [Epub ahead of print] Link to article on publisher's site
DOI
10.1038/s41375-018-0141-xPermanent Link to this Item
http://hdl.handle.net/20.500.14038/29365PubMed ID
29743725Related Resources
ae974a485f413a2113503eed53cd6c53
10.1038/s41375-018-0141-x