Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers.

Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional crosstalk in breast cancer is unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in ER-positive luminal-like breast cancer cells and represses NF-κB target gene expression by interacting with ER and directing repressive histone methylation on their promoters. Thus, EZH2 functions as a double-facet molecule in breast cancers, either as a transcriptional activator or repressor of NF-κB targets, depending on the cellular context. These findings reveal an additional mechanism by which EZH2 promotes breast cancer progression and underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.

Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis.

Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.

EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer.

Although small-molecule targeting of EZH2 appears to be effective in lymphomas carrying EZH2 activating mutations, finding similar approaches to target EZH2-overexpressing epithelial tumors remains challenging. In MYC-driven, but not PI3K-driven prostate cancer, we show that interferon-γ receptor 1 (IFNGR1) is directly repressed by EZH2 in a MYC-dependent manner and is downregulated in a subset of metastatic prostate cancers. EZH2 knockdown restored the expression of IFNGR1 and, when combined with IFN-γ treatment, led to strong activation of IFN-JAK-STAT1 tumor-suppressor signaling and robust apoptosis. Pharmacologic depletion of EZH2 by the histone-methylation inhibitor DZNep mimicked the effects of EZH2 knockdown on IFNGR1 induction and delivered a remarkable synergistic antitumor effect with IFN-γ. In contrast, although they efficiently depleted histone Lysine 27 trimethylation, EZH2 catalytic inhibitors failed to mimic EZH2 depletion. Thus, EZH2-inactivated IFN signaling may represent a therapeutic target, and patients with advanced prostate cancer driven by MYC may benefit from the combination of EZH2 and IFN-γ-targeted therapy.

PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy.

UNLABELLED: Although 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1-PLK1-MYC signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance. SIGNIFICANCE: This work identifies PDK1­PLK1-MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our findings provide important insights into cancer and CSC biology and have significant therapeutic implications.

FOXQ1 regulates epithelial-mesenchymal transition in human cancers.

Epithelial-mesenchymal transition (EMT) in cancer cells plays a pivotal role in determining metastatic prowess, but knowledge of EMT regulation remains incomplete. In this study, we defined a critical functional role for the Forkhead transcription factor FOXQ1 in regulating EMT in breast cancer cells. FOXQ1 expression was correlated with high-grade basal-like breast cancers and was associated with poor clinical outcomes. RNAi-mediated suppression of FOXQ1 expression in highly invasive human breast cancer cells reversed EMT, reduced invasive ability, and alleviated other aggressive cancer phenotypes manifested in 3-dimensional Matrigel (BD Biosciences) culture. Conversely, enforced expression of FOXQ1 in differentiated human mammary epithelial cells (HMLER) or epithelial cancer cell lines provoked an epithelial to mesenchymal morphologic change, gain of stem cell-like properties, and acquisition of resistance to chemotherapy-induced apoptosis. Mechanistic investigations revealed that FOXQ1-induced EMT was associated with transcriptional inactivation of the epithelial regulator E-cadherin (CDH1). Our findings define a key role for FOXQ1 in regulating EMT and aggressiveness in human cancer.