UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response
dc.contributor.author | Huiting, L. N. | |
dc.contributor.author | Samaha, Y. | |
dc.contributor.author | Zhang, G. L. | |
dc.contributor.author | Roderick, Justine E. | |
dc.contributor.author | Li, B. | |
dc.contributor.author | Anderson, N. M. | |
dc.contributor.author | Wang, Y. W. | |
dc.contributor.author | Wang, L. | |
dc.contributor.author | Laroche, F. | |
dc.contributor.author | Choi, J. W. | |
dc.contributor.author | Liu, C. T. | |
dc.contributor.author | Kelliher, Michelle A. | |
dc.contributor.author | Feng, H. | |
dc.date | 2022-08-11T08:08:23.000 | |
dc.date.accessioned | 2022-08-23T15:53:30Z | |
dc.date.available | 2022-08-23T15:53:30Z | |
dc.date.issued | 2018-04-25 | |
dc.date.submitted | 2018-07-06 | |
dc.identifier.citation | <p>Leukemia. 2018 Apr 25. doi: 10.1038/s41375-018-0141-x. [Epub ahead of print] <a href="https://doi.org/10.1038/s41375-018-0141-x">Link to article on publisher's site</a></p> | |
dc.identifier.issn | 0887-6924 (Linking) | |
dc.identifier.doi | 10.1038/s41375-018-0141-x | |
dc.identifier.pmid | 29743725 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/29365 | |
dc.description.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. | |
dc.language.iso | en_US | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29743725&dopt=Abstract">Link to Article in PubMed</a></p> | |
dc.relation.url | https://doi.org/10.1038/s41375-018-0141-x | |
dc.subject | Acute lymphocytic leukaemia | |
dc.subject | Cancer microenvironment | |
dc.subject | Amino Acids, Peptides, and Proteins | |
dc.subject | Cancer Biology | |
dc.subject | Cell Biology | |
dc.subject | Cellular and Molecular Physiology | |
dc.subject | Hemic and Lymphatic Diseases | |
dc.subject | Neoplasms | |
dc.subject | Therapeutics | |
dc.title | UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response | |
dc.type | Journal Article | |
dc.source.journaltitle | Leukemia | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/faculty_pubs/1594 | |
dc.identifier.contextkey | 12450418 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | faculty_pubs/1594 | |
dc.contributor.department | UMass Metabolic Network | |
dc.contributor.department | Department of Molecular, Cell and Cancer Biology |