Understanding the genetic origin of cancer at the molecular level has facilitated the development of novel targeted therapies. Aberrant activation of the ErbB family of receptors is implicated in many human cancers and is already the target of several anticancer therapeutics. The use of mAbs specific for the extracellular domain of ErbB receptors was the first implementation of rational targeted therapy. The cytoplasmic tyrosine kinase domain is also a preferred target for small compounds that inhibit the kinase activity of these receptors. However, current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.

The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.

Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-β is known to induce murine FOXP3 ⁺ Treg cells, TGF-β in combination with IL-6 attenuates the induction of FOXP3 functional activities. Here we show that TCR stimuli and TGF-β signals modulate the disposition of FOXP3 into different subnuclear compartments, leading to enhanced chromatin binding in human CD4 ⁺ CD25 ⁺ regulatory T cells. TGF-β treatment increases the level of acetylated FOXP3 on chromatin and site-specific recruitment of FOXP3 on the human IL-2 promoter. However, the proinflammatory cytokine IL-6 down-regulates FOXP3 binding to chromatin in the presence of TGF-β. Moreover, histone deacetylation inhibitor (HDACi) treatment abrogates the down-regulating effects of IL-6 and TGF-β. These studies indicate that HDACi can enhance regulatory T cell function via promoting FOXP3 binding to chromatin even in a proinflammatory cellular microenvironment. Collectively, our data provide a framework of how different signals affect intranuclear redistribution, posttranslational modifications, and chromatin binding patterns of FOXP3.

The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here, we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. Furthermore, we show that the N-terminal domain of FOXC1 (aa 1-68) binds directly to an internal region (aa 898-1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.