Transcriptional Regulation of the Proteasome: Implications for Cancer Therapy

While proteasome inhibitors are being effectively used in the clinic to treat multiple myeloma and mantle cell lymphoma, the reasons for why this strategy is not generally applicable to other tumor types is poorly understood. A detailed characterization of the cellular events triggered in response to these agents could offer vital clues to target the protein degradation pathway(s) more effectively in a broad range of tumors. Our previous studies have established the transcription factor Nrf1 as a key player in the stress‐response pathway invoked by inhibition of cellular proteasome. Nrf1, by its ability to induce de novo synthesis of proteasome subunit genes in response to proteasome inhibitors, promotes the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing cellular survival. From a therapeutic stand‐point, this suggests that disabling the Nrf1‐mediated proteasome recovery pathway could potentiate the action of proteasome inhibitor treatments. However, effective means to curb the Nrf1 pathway remain scarce. Here, using an in silico chemical biology approach, we uncovered a class of therapeutic agents that can effectively inhibit the Nrf1 pathway. Mechanistic dissection of this phenomenon provided further novel insight into the way by which Nrf1 maintains its transcriptional activity. Using triple negative breast cancer (TNBC) cell lines and patient‐derived xenograft (PDX) models, we further validated our hypothesis that attenuating the Nrf1 pathway could increase the efficacy of proteasome inhibitor therapeutics. Thus, our study sheds light on the unique biology of Nrf1 along with validating this pathway as a therapeutic target in TNBC. This could serve as a motivation for similar future efforts where Nrf1 pathway inhibitors can be tested as adjuvants for proteasome inhibitor treatments in other cancer types. Support or Funding Information NIH grant R01GM132396