The proteasome inhibitor bortezomib is a potent inducer of zinc-finger AN1-type domain 2a gene expression: role of HSF1/HSF2 heterocomplexes [Gene Regulation]
March 11th, 2014 by Rossi, A., Riccio, A., Coccia, M., Trotta, E., La Frazia, S., Santoro, M. G.
The zinc-finger AN1-type domain 2a gene, also known as AIRAP, was recently identified as a novel human canonical heat shock gene, strictly controlled by heat shock factor-1 (HSF1). Little is known about AIRAP gene regulation in human cells. Herein we report that bortezomib, a proteasome inhibitor with anticancer and antiangiogenic properties used in the clinic for treatment of multiple myeloma, is a potent inducer of AIRAP expression in human cells. Using endothelial cells as a model, we unraveled the molecular mechanism regulating AIRAP expression during proteasome inhibition. Bortezomib induces AIRAP expression at the transcriptional level early after treatment, concomitantly with polyubiquitinated proteins accumulation and HSF activation. AIRAP protein is detected at high levels for at least 48 h after bortezomib exposure, together with the accumulation of heat shock factor-2 (HSF2), a factor implicated in differentiation and development regulation. Differently from heat-mediated induction, in bortezomib-treated cells HSF1 and HSF2 directly interact forming HSF1/HSF2 heterotrimeric complexes recruited to a specific heat shock element in the AIRAP promoter. Interestingly, while HSF1 was confirmed to be critical for AIRAP gene transcription, HSF2 was found to negatively regulate AIRAP expression after bortezomib treatment, further emphasizing an important modulatory role of this transcription factor under stress conditions. AIRAP function is still not defined; however, the fact that AIRAP is abundantly expressed in primary human cells at bortezomib concentrations comparable to plasma-levels in treated patients suggests that AIRAP may participate in the regulatory network controlling proteotoxic stress during bortezomib treatment.