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

Link to Article in PubMed

Journal/Book/Conference Title

Leukemia

PubMed ID

29743725

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