Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

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. RNAimediated 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. Cancer Res; 71(8); 3076-86. Ó2011 AACR.

BackgroundVirtual patient simulation has grown substantially in health care education. A virtual patient simulation was developed as a refresher training course to reinforce nursing clinical performance in assessing and managing deteriorating patients.ObjectiveThe objective of this study was to describe the development of the virtual patient simulation and evaluate its efficacy, by comparing with a conventional mannequin-based simulation, for improving the nursing students’ performances in assessing and managing patients with clinical deterioration.MethodsA randomized controlled study was conducted with 57 third-year nursing students who were recruited through email. After a baseline evaluation of all participants’ clinical performance in a simulated environment, the experimental group received a 2-hour fully automated virtual patient simulation while the control group received 2-hour facilitator-led mannequin-based simulation training. All participants were then re-tested one day (first posttest) and 2.5 months (second posttest) after the intervention. The participants from the experimental group completed a survey to evaluate their learning experiences with the newly developed virtual patient simulation.ResultsCompared to their baseline scores, both experimental and control groups demonstrated significant improvements (P<.001) in first and second post-test scores. While the experimental group had significantly lower (P<.05) second post-test scores compared with the first post-test scores, no significant difference (P=.94) was found between these two scores for the control group. The scores between groups did not differ significantly over time (P=.17). The virtual patient simulation was rated positively.ConclusionsA virtual patient simulation for a refreshing training course on assessing and managing clinical deterioration was developed. Although the randomized controlled study did not show that the virtual patient simulation was superior to mannequin-based simulation, both simulations have demonstrated to be effective refresher learning strategies for improving nursing students’ clinical performance. Given the greater resource requirements of mannequin-based simulation, the virtual patient simulation provides a more promising alternative learning strategy to mitigate the decay of clinical performance over time.

The molecular mechanisms underlying constitutive nuclear factor-jB (NF-jB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-jB activity, suggesting that ANXA1 may be required for the constitutive activity of IjB kinase (IKK) and NF-jB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-jB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKc or NEMO, but not IKKa or IKKb. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-jB. Downstream targets of NF-jB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-jB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-jB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-jB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.

Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this “Poised Gene Cassette” (PGC) was robustly validated across 11 independent cohorts of ∼1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies.

The significance of fatty acid metabolism in cancer initiation and development is increasingly accepted by scientists and the public due to the high prevalence of overweight and obese individuals. Fatty acids have different turnovers in the body: Either breakdown into acetyl-CoA to aid ATP generation through catabolic metabolism or incorporation into triacylglycerol and phospholipid through anabolic metabolism. However, these two distinct pathways require a common initial step known as fatty acid activation. Long-chain acyl-CoA synthetases (ACSLs), which are responsible for activation of the most abundant long-chain fatty acids, are commonly deregulated in cancer. This deregulation is also associated with poor survival in patients with cancer. Fatty acids physiologically regulate ACSL expression, but cancer cells could hijack certain involved regulatory mechanisms to deregulate ACSLs. Among the five family isoforms, ACSL1 and ACSL4 are able to promote ungoverned cell growth, facilitate tumor invasion and evade programmed cell death, while ACSL3 may have relatively complex functions in different types of cancer. Notably, ACSL4 is also essential for the induction of ferroptosis (another form of programmed cell death) by facilitating arachidonic acid oxidation, which makes the enzyme a desirable cancer target. The present review thus evaluates the functions of deregulated ACSLs in cancer, the possible molecular mechanisms involved and the chemotherapeutic potentials to target ACSLs. A better understanding of the pathological effects of ACSLs in cancer and the involved molecular mechanisms will aid in delineating the exact role of fatty acid metabolism in cancer and designing precise cancer prevention and treatment strategies.

The PP2A serine/threonine protein phosphatase serves as a critical cellular regulator of cell growth, proliferation, and survival. However, how this pathway is altered in human cancer to confer growth advantage is largely unknown. Here, we show that PPP2R2B, encoding the B55β regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55β-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. On loss of PPP2R2B, mTORC1 inhibitor rapamycin triggers a compensatory Myc phosphorylation in PDK1-dependent, but PI3K and AKT-independent manner, resulting in resistance. Reexpression of PPP2R2B, genetic ablation of PDK1 or pharmacologic inhibition of PDK1 abrogates the rapamycin-induced Myc phosphorylation, leading to rapamycin sensitization. Thus, PP2A-B55β antagonizes PDK1-Myc signaling and modulates rapamycin sensitivity.

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression.