SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

The capacity of the liver to regenerate is likely to be encoded as a plasticity of molecular networks within the liver. By applying a combination of comprehensive analyses of the epigenome, transcriptome, and proteome, we herein depict the molecular landscape of liver regeneration. We demonstrated that histone H3 Lys-4 was trimethylated at the promoter regions of many loci, among which only a fraction, including cell-cycle-related genes, were transcriptionally up-regulated. A cistrome analysis guided by the histone methylation patterns and the transcriptome identified FOXM1 as the key transcription factor promoting liver regeneration, which was confirmed in vitro using a hepatocarcinoma cell line. The promoter regions of cell-cyclerelated genes and Foxm1 acquired higher levels of trimethylated histone H3 Lys-4, suggesting that epigenetic regulations of these key regulatory genes define quiescence and regeneration of the liver cells. A quantitative proteome analysis of the regenerating liver revealed that conditional protein degradation also mediated regeneration-specific protein expression. These sets of informational resources should be useful for further investigations of liver regeneration.

Section: The Integration Of the Cistrome And The Transcriptome Pointsmentioning

confidence: 92%

Regulatory signatures of liver regeneration distilled by integrative analysis of mRNA, histone methylation, and proteomics

Sato¹,

Katoh²,

Matsumoto³

et al. 2017

“…cDNA was generated using the Applied Biosystems High Capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, CA). Evaluation of expression levels of specific genes was performed by qRT-PCR using inventoried TaqMan probes (Table 2) and the StepOnePlus real-time PCR system (Applied Biosystems, Foster City, CA) as described previously (37)(38)(39)(40)(41)(42).…”

Section: Primer Name Sequencementioning

confidence: 99%

Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

Bolte

Ren

Tomley

et al. 2015

Self Cite

Background: Transcriptional regulation of smooth muscle cells is an understudied component of intestinal development and physiology. Results: Foxf2 deletion from smooth muscle causes intestinal malformations and colon remodeling. Conclusion: Foxf2 regulation of PDGF and myocardin/SRF signaling is essential for intestinal development and homeostasis. Significance: Better understanding of transcriptional mechanisms regulating postnatal intestine development and homeostasis may provide therapeutic approaches for congenital and acquired gastrointestinal diseases.

“…They showed that the tumor suppressor SPDEF competed with FOXM1 for the FOXM1 binding site responsible for the autoregulation of FOXM1. Furthermore, SPDEF inhibited FOXM1 expression and consequently cancer development in a mouse model of prostate cancer (33). These data suggest that the autoregulation of FOXM1 might be required for cancer development and could be a promising target for anticancer treatment.…”

Section: Discussionmentioning

confidence: 74%

“…1 and 4E). Recently, Cheng et al (33) confirmed the importance of FOXM1 autoregulation for cancer development (34). They showed that the tumor suppressor SPDEF competed with FOXM1 for the FOXM1 binding site responsible for the autoregulation of FOXM1.…”

Section: Discussionmentioning

confidence: 96%

A Novel Function of Molecular Chaperone HSP70

Halasi¹,

Váraljai

Benevolenskaya

et al. 2016

The oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers, and it is a potential target for anticancer therapy. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1. The common effector, which was induced after treatment with proteasome and HSP90 inhibitors or heat shock, was the molecular chaperone HSP70. We show that HSP70 binds to FOXM1 following proteotoxic stress and that HSP70 inhibits FOXM1 DNA-binding ability. Inhibition of FOXM1 transcriptional autoregulation by HSP70 leads to the suppression of FOXM1 protein expression. In addition, HSP70 suppression elevates FOXM1 expression, and simultaneous inhibition of FOXM1 and HSP70 increases the sensitivity of human cancer cells to anticancer drug-induced apoptosis. Overall, we determined the unique and novel mechanism of FOXM1 suppression by proteasome inhibitors.Forkhead Box M1 (FOXM1) is an oncogenic transcription factor that is also a well recognized cell cycle regulator (1). FOXM1 expression is eliminated from quiescent or differentiated cells, but it is highly expressed in proliferating and malignant cells (1). It is also well documented that FOXM1 is overexpressed in broad types of human cancers and it contributes to several aspects of cancer development (2, 3). Consequently, it is not surprising that FOXM1 has evolved as a potential target of anticancer therapy (4).Our group identified the thiazole antibiotics Siomycin A (5) and thiostrepton (6) as the first chemical inhibitors of FOXM1. Investigation of their mechanism of action revealed that they are proteasome inhibitors (7). Bona fide proteasome inhibitors, including MG132 and bortezomib, have also been found to hinder the transcriptional activity and expression of FOXM1 (7), suggesting that FOXM1 is one of the general targets of these drugs. Proteasome inhibitors stabilize the expression of cellular proteins. Therefore, suppression of FOXM1 is counterintuitive and has not been well understood. As an explanation for this effect, we put forward the hypothesis that a negative regulator of FOXM1 (NRFM) 2 is stabilized by proteasome inhibitors (8), which directly or indirectly inhibits FOXM1 transcriptional activity (9). Here we determined that the NRFM is HSP70. Because a positive autoregulation loop is required for FOXM1 expression (9), HSP70 (NRFM) also represses FOXM1 mRNA and protein expression after treatment with proteasome inhibitors.Heat shock proteins (HSPs) are stress proteins that are mainly expressed in response to different cellular and environmental insults. HSPs are divided by their molecular weight into the subfamilies HSP110, HSP90, HSP70, HSP60, and small HSPs. Besides their major function of aiding protein folding as molecular chaperones, HSPs also play important roles in cell signaling, protein trafficking, and blocking cell death (10 -13). Elevated levels of HSPs are linked not only to cytoprotection but to neurodegenerative ...