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Definition of a transcriptional signature of proteasome stress across cell types and its occurrence with aging [RNA-Seq human]

ABSTRACT: The proteasome is key for maintaining cellular homeostasis by ensuring protein turnover. Proteasome inhibition triggers a compensatory increase in proteasome gene expression, but it is largely undetermined whether this is the primary response induced by proteasome inhibition. Here, we profiled the transcriptional changes induced by chemical and genetic proteasome inhibition. By examining the time-dose response to proteasome inhibition in cells and organoids, we find that modulation of proteasome gene expression varies in a context-dependent manner, and that other categories are more prominently and consistently regulated by proteasome inhibition. These include upregulation of chaperones and secreted factors, and downregulation of cell cycle regulators. Moreover, we define a proteasome stress response signature based on genes that are significantly and consistently modulated by proteasome inhibition across different cell systems. Some tissues (e.g., skeletal muscle) display an age-associated modulation of this signature consistent with age-activation of the proteasome stress response. Collectively, our study provides a global analysis of transcriptional changes induced by proteasome inhibition, and defines a transcriptional signature of proteasome stress that can be utilized to monitor the activation of this stress response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312866 | GEO | 2026/08/26

REPOSITORIES: GEO

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Project description:Oncogenic growth typically places great strain and dependence on protein homeostasis (proteostasis) pathways. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug components of these pathways have yielded largely disappointing clinical outcomes. One notable exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. Despite this success, proteasome inhibitors are largely ineffective in the treatment of other cancers, including acute myeloid leukemia (AML), although the reasons for these cancer-specific differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to their inability to disrupt proteostasis. In response to proteasome inhibition, human AML cells activated heat shock factor 1 (HSF1) and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized multiple human AML cell lines to proteasome inhibition, marked by accumulation of unfolded protein and activation of the PERK-mediated integrated stress response. This response was associated with severe reductions in protein synthesis, proliferation and cell survival in vitro and significant slowing of disease progression and extension of survival in AML xenografts in vivo. Similarly, pharmacological inhibition of autophagy sensitized human AML cells to proteasome inhibition by disrupting proteostasis. Combined autophagy and proteasome inhibition suppressed proliferation and synergistically killed human AML cells in vitro, and significantly reduced AML burden and extended survival in vivo. Furthermore, combined autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including CD34+ AML stem and progenitor cells, without severely affecting normal hematopoietic stem and progenitor cells. Effects of combined autophagy and proteasome inhibition were associated with induction of a terminal integrated stress response, which, surprisingly, was not driven by a canonical unfolded protein response, but rather by Protein kinase R (PKR). Overall, these studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

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Definition of a transcriptional signature of proteasome stress across cell types and its occurrence with aging [RNA-Seq human]

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