Transcriptomics

Dataset Information

3

Increased Protein Processing Gene Signature in HDACi-resistant cells predicts response to proteasome inhibitors.


ABSTRACT: Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL). Importantly, genetics abnormalities lead to inactivation of HAT, which tilt the balance in favor of decreased protein acetylation in DLBCL cells. This suggests that protein acetylation regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to the histone deacetylase inhibitor (HDACi) vorinostat, in order to better define molecular mechanisms of action of HDACi in lymphoma cells. We found that cells resistant to HDACi have increased protein synthesis and proteasomal degradation. Additionally, cells resistant to HDACi have acquired increased susceptibility to proteasome inhibitors and this correlates with activation of the unfolded protein response. Importantly, using transcriptional signatures found in our resistant lymphoma cell line model, we show that tumors from DLBCL patients treated but unresponsive to HDACi therapy undergo similar changes. Together, these data show, for the first time, that HDACi may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in U937 cells after 12h exposure to 2µM vorinostat and after development of resistance to 2 µM vorinostat, with and without vorinostat in the media.

ORGANISM(S): Homo sapiens  

SUBMITTER: Koren Mann   Koren K Mann  Wilson H Miller Jr 

PROVIDER: E-GEOD-58421 | ArrayExpress | 2016-06-01

SECONDARY ACCESSION(S): GSE58421PRJNA252564

REPOSITORIES: GEO, ArrayExpress

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