No abstract

Flavonols are a flavonoid subfamily widely distributed in plants, including several ones of great importance in human and animal diet (apple, tomato, broccoli, onion, beans, tea). These polyphenolic nutraceuticals exert potent antimicrobial (membrane potential disruptors), antioxidant (free-radical scavengers), pharmacokinetic (CYP450 modulators), anti-inflammatory (lipoxygenase inhibitors), antiangiogenic (VEGF inhibitors) and antitumor (cyclin inhibitors) activities. Biotechnological production of these nutraceuticals, for example via heterologous biosynthesis in industrial actinomycetes, is favored since in plants these polyphenols appear as inactive glycosylated derivatives, in low concentrations or as part of complex mixtures with other polyphenolic compounds. In this work, we describe the de novo biosynthesis of three important flavonols, myricetin, kaempferol and quercetin, in the industrially relevant actinomycetes Streptomyces coelicolor and S. albus. De novo biosynthesis of kaempferol, myricetin and quercetin in actinomycetes has not been described before.

The transcription factor FOSL1 is upregulated in human and mouse CCA, and is independently associated with patient survival. Genetic FOSL1 inhibition impairs cell proliferation and cell cycle progression in vitro, and tumor initiation and maintenance in vivo.The mevalonate pathway gene HMGCS1 is upregulated in human and mouse CCA, and its expression is controlled by direct FOSL1 promoter binding.Genetic HMGCS1 abrogation or pharmacological blockade with mTOR inhibitors phenocopies loss of FOSL1.

Study approval. All experiments in mice were performed according to the MD Anderson Cancer Center Institutional Animal Care and Use Committee (IACUC, protocol 00001636), UCSF Committee on Animal Care (APLAC), and the University of Navarra Ethical Committee on Animal Research (CEEA, protocol 068-13). Regarding human data, only normalized/processed data of coded clinical information were made available to this study to preserve patients' anonymity.