title: Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers.
abstract: The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; petert@wi.mit.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Tsvetkov
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Ethan
authors.initials: E
authors.lastname: Sokol
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Dexter
authors.initials: D
authors.lastname: Jin
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Zarina
authors.initials: Z
authors.lastname: Brune
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.affiliation: Broad Institute, Cambridge, MA 02142.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: Broad Institute, Cambridge, MA 02142.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Koch Institute for Integrative Cancer Research, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02138.
authors.forename: Piyush B
authors.initials: PB
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Howard Hughes Medical Institute, Cambridge, MA 02139.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: EMT; apoptosis; bortezomib; drug resistance; epigenetic gene regulation