Fabermccain2744

Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here we sought to systematically characterize the division of labor between YAP and TAZ in non-small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Representative NSCLC cell lines as well as patient-derived data showed that the two paralogs orchestrated nonoverlapping transcriptional programs in this cancer type. YAP preferentially regulated gene sets associated with cell division and cell-cycle progression, whereas TAZ preferentially regulated genes associated with extracellular matrix organization. Depletion of YAP resulted in growth arrest, whereas its overexpression promoted cell proliferation. Likewise, depletion of TAZ compromised cell migration, whereas its overexpression enhanced migration. The differential effects of YAP and TAZ on key cellular processes were also associated with differential response to anticancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of patients with lung cancer for anticancer therapies. SIGNIFICANCE Thease findings show that oncogenic paralogs YAP and TAZ have distinct roles in NSCLC and are associated with differential response to anticancer drugs, knowledge that may assist lung cancer therapy decisions.Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. Orelabrutinib TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.Tight junction (TJ) proteins are essential for mediating interactions between adjacent cells and coordinating cellular and organ responses. Initial investigations into TJ proteins and junctional adhesion molecules (JAM) in cancer suggested a tumor-suppressive role where decreased expression led to increased metastasis. However, recent studies of the JAM family members JAM-A and JAM-C have expanded the roles of these proteins to include protumorigenic functions, including inhibition of apoptosis and promotion of proliferation, cancer stem cell biology, and epithelial-to-mesenchymal transition. JAM function by interacting with other proteins through three distinct molecular mechanisms direct cell-cell interaction on adjacent cells, stabilization of adjacent cell surface receptors on the same cell, and interactions between JAM and cell surface receptors expressed on adjacent cells. Collectively, these diverse interactions contribute to both the pro- and antitumorigenic functions of JAM. In this review, we discuss these context-dependent functions of JAM in a variety of cancers and highlight key areas that remain poorly understood, including their potentially diverse intracellular signaling networks, their roles in the tumor microenvironment, and the consequences of posttranslational modifications on their function.