Targeting FOXM1 auto-regulation in cancer

FOXM1 is an oncogenic transcription factor of the Forkhead family that is overexpressed in more than 20 types of human cancer.¹ Recent experimental data suggest that FOXM1¹ is implicated in all hallmarks of cancer.² The oncogenic potential of FOXM1 is primarily based on its ability to act as a transcriptional activator. Previously, we identified inhibitors of FOXM1, the thiazole antibiotics siomycin A and thiostrepton.^3,4 We found that they act as proteasome inhibitors and inhibit transcriptional activity of FOXM1.^4,5 To our surprise, these drugs also inhibited the mRNA and protein expression of FOXM1.^3,4 Later we explained these data by the discovery of a FOXM1 auto-regulation loop ⁵, whereby FOXM1 binds to its own promoter (unpublished data) and induces its own expression.⁶ Because FOXM1 activates its own transcription ⁶, inhibition of FOXM1 transcriptional activity by proteasome inhibitors leads to a decrease of FOXM1 expression.⁷ We proposed that proteasome inhibitors stabilize a negative regulator of FOXM1 (NRFM) that interacts with FOXM1 and inhibits FOXM1 transcriptional activity.⁸ Because of the FOXM1 auto-regulation loop, inhibition of FOXM1 transcriptional activity leads to suppression of FOXM1 expression.^9,10 Therefore, the suppression of FOXM1 by the only known class of drugs that target FOXM1 (proteasome inhibitors) ⁵ is based on the FOXM1 auto-regulatory loop.

Recently, Cheng and colleagues provided new insight about the importance of the FOXM1 auto-regulation in prostate cancer.¹¹ They demonstrated that tumor–suppressor SPDEF (SAM-pointed domain-containing ETS transcription factor) inhibited the FOXM1 auto-regulation loop and FOXM1 expression, and suppressed carcinogenesis in the TRAMP model of prostate cancer.¹¹ This is the first evidence that auto-regulation of FOXM1 might be required for development of some types of cancer and could be a target of anticancer treatment.

Kalin and colleagues showed previously that FOXM1 accelerated progression of prostate cancer in mouse models.¹² In the current paper the authors addressed the role of SPDEF in the prostate cancer development. They showed that loss-of-function of SPDEF in mouse prostate epithelium correlated with increased FOXM1 activity and prostate cancer progression. In contrast, transgenic mice with the gain-of-function of SPDEF exhibited reduced proliferation of prostate cancer cells in vivo and in vitro, as well, as loss of FOXM1 activity. Over-expression of SPDEF led to down-regulation of FOXM1 target genes, such as, Cdc25b, Cyclin B1, Plk-1, Aurora B, etc. These data suggested that SPDEF inhibited FOXM1 in prostate cancer, but the mechanism of this inhibition was very unusual. They showed that SPDEF binds to the auto-regulatory FOXM1 binding site located within −745/−660 bp of the Foxm1 promoter region and inhibits FOXM1 binding to this site. As a result, FOXM1 was unable to induce its own transcription, which led to suppression of FOXM1 expression. Suppression of FOXM1 expression inhibited proliferation of prostate cancer cells, while re-expression of FOXM1 restored prostate cancer cell proliferation in the SPDEF- positive mouse prostate tumors. These data suggest that auto-regulation of FOXM1 is required for prostate cancer development in TRAMP model.

Future experiments are needed to determine whether the FOXM1 auto-regulation loop is a common requirement for development of human cancer. If FOXM1 auto-regulation is required for growth of different types of human cancer, it may change the paradigm of their treatment. Different approaches could be used to target the FOXM1 auto-regulation loop to inhibit human cancer growth. Small molecules or short peptides that inhibit FOXM1 binding to its own promoter could be used. Alternatively, decoy oligonucleotides ¹³ that mimic the FOXM1 DNA-binding site will compete for FOXM1 binding could be used to inhibit FOXM1 transcriptional activity and expression. The paper of Cheng and colleagues reminded us about importance of FOXM1 in cancer and pointed out on potentially new ways to target FOXM1.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

Funding for this manuscript was provided by the National Institutes of Health (5R01CA138409).