University of Massachusetts Medical School Faculty Publications
Title
UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response
UMMS Affiliation
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Publication Date
2018-04-25
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Hemic and Lymphatic Diseases | Neoplasms | Therapeutics
Abstract
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.
Keywords
Acute lymphocytic leukaemia, Cancer microenvironment
DOI of Published Version
10.1038/s41375-018-0141-x
Source
Leukemia. 2018 Apr 25. doi: 10.1038/s41375-018-0141-x. [Epub ahead of print] Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Leukemia
PubMed ID
29743725
Repository Citation
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.; and Feng, H., "UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response" (2018). University of Massachusetts Medical School Faculty Publications. 1594.
https://escholarship.umassmed.edu/faculty_pubs/1594