Long non-coding RNAs (lncRNAs) govern fundamental biochemical and cellular processes. lncRNA HOX transcript antisense RNA (HOTAIR) represses gene expression through recruitment of chromatin modifiers. The expression of HOTAIR is elevated in lung cancer and correlates with metastasis and poor prognosis. Moreover, HOTAIR promotes proliferation, survival, invasion, metastasis, and drug resistance in lung cancer cells. Here we review the molecular mechanisms underlying HOTAIR-mediated aggressive phenotypes of lung cancer. We also discuss HOTAIR’s potential in diagnosis and treatment of lung cancer, as well as the challenges of exploiting HOTAIR for intervention of lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0090-4) contains supplementary material, which is available to authorized users.

Nonribosomal peptides are amongst the most widespread and structurally diverse secondary metabolites in nature with many possessing bioactivity that can be exploited for therapeutic applications. Due to the major challenges associated with total- and semi-synthesis, bioengineering approaches have been developed to increase yields and generate modified peptides with improved physicochemical properties or altered bioactivity. Here we review the major advances that have been made over the last decade in engineering the biosynthesis of nonribosomal peptides. Structural diversity has been introduced by the modification of enzymes required for the supply of precursors or by heterologous expression of tailoring enzymes. The modularity of nonribosomal peptide synthetase (NRPS) assembly lines further supports module or domain swapping methodologies to achieve changes in the amino acid sequence of nonribosomal peptides. We also review the new synthetic biology technologies promising to speed up the process, enabling the creation and optimisation of many more assembly lines for heterologous expression, offering new opportunities for engineering the biosynthesis of novel nonribosomal peptides.

The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of Ϸ20,000 microbial extracts, 12 hits were identified with broadspectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.antifungal ͉ beauvericin ͉ ketoconazole

The aberrant expression of transforming growth factor (TGF)-␤1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-␤1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including ␣-tubulin, and regulates cell motility. We showed that TGF-␤1-induced EMT is accompanied by HDAC6-dependent deacetylation of ␣-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-␤1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-␤1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of ␣-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-␤-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis. Epithelial-mesenchymal transition (EMT)2 is defined as a series of events through which epithelial cells lose many of their epithelial characteristics and acquire properties that are typical of mesenchymal cells (1). Aberrant EMT has been well documented in chronic fibrosis in multiple organs and carcinoma progression. During progression to metastatic competence, carcinoma cells acquire mesenchymal gene expression patterns and properties through EMT, which results in coordinated alterations in adhesive properties, activation of proteolysis and motility, and competence to metastasize and establish secondary tumors at distant sites (1). Fibrosis is characterized by an increased number of myofibroblasts that deposit interstitial extracellular matrix. Mounting evidence indicates that a significant fraction of these myofibroblasts arise from the resident epithelial cells via EMT during renal and lung fibrogenesis (2-6).Family members of transforming growth factor (TGF)-␤ are among the most potent inducers of EMT in a variety of physiological and pathological contexts (7). The aberrant expression of TGF-␤1 is well documented in the tumor microenvironment and fibrotic lesions where TGF-␤1 is widely believed to promote tumor progression and tissue fibrosis (7). Several recent studies have elegantly demonstrated EMT of lung alveolar epithelial cells in biopsies from patients with idiopathic pulmonary fibrosis and in experimental pulmonary fibrosis (4,5,8). A host of evidence indicates an essential role for SMAD3 in the expression of a panel of EMT-related genes upon translocation into the nucleus (9). The molecular me...