BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAFV600E–a mutation found in ∼10% of human prostate tumors–was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies

The Msx1 Homeoprotein Recruits G9a Methyltransferase to Repressed Target Genes in Myoblast Cells

Although the significance of lysine modifications of core histones for regulating gene expression is widely appreciated, the mechanisms by which these modifications are incorporated at specific regulatory elements during cellular differentiation remains largely unknown. In our previous studies, we have shown that in developing myoblasts the Msx1 homeoprotein represses gene expression by influencing the modification status of chromatin at its target genes. We now show that genomic binding by Msx1 promotes enrichment of the H3K9me2 mark on repressed target genes via recruitment of G9a histone methyltransferase, the enzyme responsible for catalyzing this histone mark. Interaction of Msx1 with G9a is mediated via the homeodomain and is required for transcriptional repression and regulation of cellular differentiation, as well as enrichment of the H3K9me2 mark in proximity to Msx1 binding sites on repressed target genes in myoblast cells as well as the developing limb. We propose that regulation of chromatin status by Msx1 recruitment of G9a and other histone modifying enzymes to regulatory regions of target genes represents an important means of regulating the gene expression during development

Homeobox genes and cancer New OCTaves for an old tune

AbstractIn this issue of Cancer Cell, Gidekel et al. demonstrate that Oct-4, a member of the POU class of homeobox genes, is a critical player in the genesis of testicular germ cell tumors. This study provides further evidence that deregulated expression of homeobox genes, which occurs in many solid tumors, is functionally relevant for carcinogenesis and highlights unique features that distinguish homeobox genes from other cancer-promoting genes

Working model.

<p>As described in the text, we have proposed that binding of the Msx1 homeoprotein to specific target genes brings G9a and/or Ezh2 to the regulatory regions of these genes to influence histone modifications. According G9a and Ezh2 bound status, the Msx1 bound and down-regulated target genes were categorized in 4 categories. (A) Category I, Msx1 brings G9a and Ezh2 to the same site on target genes. (B) Category II, Msx1 brings G9a and Ezh2 to the same target genes but at different sites. (C) Category III, Msx1 only brings Ezh2 to the Msx1 bound site on target genes. (D) Category IV, Msx1 do not brings ether G9a or Ezh2 to the target genes, but Msx1 may brings other factors to Msx1 bound site to repress target genes expression.</p

Msx1 genomic binding associates with enrichment of the H3K9me2 repressive mark in myoblast cells.

<p>(A) Diagram of six Msx1 repressed target genes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037647#pone.0037647-Wang1" target="_blank">[23]</a> showing the positions of Msx1 binding sites and known regulatory regions as well as their overlap; also shown is a negative control site. DRR: Distal Regulatory Region. (B) ChIP-qPCR analyses showing the relative levels of H3K9me2 at Msx1 genomic binding sites in C2C12 cells. ChIP data are expressed as relative enrichment of H3K9me2 normalized to input in C2C12 cells expressing or lacking Msx1. <i>(Inset)</i> ChIP data expressed as fold enrichment of H3K9me2 in C2C12 cells expressing Msx1 versus the control cells lacking Msx1 (and normalized to input). (C) ChIP-qPCR assays were done using C2C12 cells expressing Flag-Msx1 or a control vector to evaluate binding of G9a to the indicated Msx1 target sequences. ChIP data are expressed as relative enrichment of G9a binding normalized to input in C2C12 cells expressing or lacking Msx1. <i>(Inset)</i> ChIP data are expressed as fold enrichment of G9a binding in C2C12 cells expressing Msx1 versus the control cells lacking Msx1 (and normalized to input). In B and C, the * indicate the following: ***<i>P</i><0.0001, **<i>P</i><0.001, *<i>P</i><0.01.</p