Correspondence to: Andrei L. Gartel; Email: agartel@ uic. edu Submitted: 10/25/11; Accepted: 10/26/11 http://dx. doi. org/10.4161/cc. 10.24. 18544 (unpublished data) and induces its own transcription and protein expression. 8 Most importantly, we showed that all PIs that were tested so far (from canonical, such as bortezomib, MG132, MG115 and lactacystin, to recently identified, such as PEITC10) affect FOXM1 the same way as thiostrepton/Siomycin A. Based on these data, we proposed the following model of FOXM1 suppression by PIs, including thiostrepton: 11 all PIs stabilize a negative regulator of FOXM1 (NRFM) that binds to FOXM1 or acts otherwise to inhibit transcriptional activity of FOXM1 on its target promoters, including the FOXM1 promoter, because of the FOXM1 autoregulation loop. As a consequence of inhibition of FOXM1 transcriptional activity on its own promoter, we observed suppression of FOXM1 mRNA and protein after treatment with PIs. 6, 7 This hypothesis may explain why all tested PIs suppress FOXM1 transcriptional activity and expression independently of their structures (via stabilization of NRFM). In contrast, Hegde et al. 3 suggest that direct binding of thiostrepton to FOXM1 is the reason for inhibition of FOXM1 transcriptional activity and expression by thiostrepton. However, thiostrepton is just one of several PIs that regulate FOXM1, and if this explanation is correct, it should also be correct for other PIs that affect FOXM1. In this case, we need to predict direct binding of all PIs to FOXM1. Since different PIs have absolutely different structures, it is unlikely that all of them will directly interact with FOXM1. Therefore, I believe that a common feature of PIs, stabilization of proteins, particularly of NRFM, may explain their effects on FOXM1. At the same time, there is no doubt that thiostrepton directly binds to FOXM1, but this binding may not have functional significance for modulation of FOXM1 activity. For example, experiments that suggest that thiostrepton prevents binding of FOXM1 to target promoters by direct binding to FOXM1 (Fig. 4C of the paper) could be also explained by using our model of stabilization of NRFM that inhibits transcriptional activity of FOXM1. In addition, it is not clear how the authors of this paper may explain the fact that thiostrepton, after binding to FOXM1, inhibits FOXM1 protein expression5 (Fig. 4A of the paper) if, by their CHIP assay, FOXM1 is not binding to the FOXM1 promoter (Fig. 4D of the paper). It will be possible to give a direct answer for functional significance of thiostrepton/FOXM1 binding after identification of NRFM and its inactivation by RNA interference. Since proteasome inhibitors are an important class of anticancer drugs and suppression of FOXM1 is one of key mechanisms of action of these drugs, we think that it is essential to discuss the mechanism by which thiostrepton and other proteasome inhibitors may affect FOXM1. Additional experiments are needed to address the functional significance of direct binding of thiostrepton to FOXM1 in the context of regulation of FOXM1 by all proteasome inhibitors. Unfortunately, authors of this paper declined to provide a rebuttal, suggesting that they have nothing to say in response to our comments. Subsequently, the editors refused to publish this correspondence in Nature Chemistry, because they think it would not add anything to our understanding of regulation of FOXM1 by thiostrepton “and would not clarify this issue in the minds of the nonspecialist readers of Nature Chemistry.” Hopefully, our letter will add new information and will raise new questions for the readers of Cell Cycle.