Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine

Potent Anti-Cancer Properties of Phthalimide-Based Curcumin Derivatives on Prostate Tumor Cells

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess improved stability, pharmacodynamics, and radical scavenging ability. To investigate the potential application in anti-cancer therapy, the anti-proliferative activity of the synthesized molecules was determined on aggressive prostate tumor cells. We demonstrated that the K3F21 derivative has increased potency compared to curcumin, in terms of GI50, anti-proliferative and anti-migrating activities. K3F21 inhibits anchorage-dependent and -independent growth of prostate cancer cells by altering the expression of key genes controlling cell proliferation, such as Cylins D1, B1 and B2, and apoptosis, among which Puma, Noxa, and Bcl-2 family members. Finally, the anti-cancer activity of K3F21 was demonstrated by the analysis of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways

Nutraceuticals and Herbal Food Supplements for Weight Loss: Is There a Prebiotic Role in the Mechanism of Action?

Numerous nutraceuticals and botanical food supplements are used with the intention of modulating body weight. A recent review examined the main food supplements used in weight loss, dividing them according to the main effects for which they were investigated. The direct or indirect effects exerted on the intestinal microbiota can also contribute to the effectiveness of these substances. The aim of this review is to evaluate whether any prebiotic effects, which could help to explain their efficacy or ineffectiveness, are documented in the recent literature for the main nutraceuticals and herbal food supplements used for weight loss management. Several prebiotic effects have been reported for various nutraceutical substances, which have shown activity on Bifidobacterium spp., Lactobacillus spp., Akkermansia muciniphila, Faecalibacterium prausnitzi, Roseburia spp., and the Firmicutes/Bacteroidetes ratio. Different prebiotics have beneficial effects on weight and the related metabolic profile, in some cases even acting on the microbiota with mechanisms that are completely independent from those nutraceuticals for which certain products are normally used. Further studies are necessary to clarify the different levels at which a nutraceutical substance can exert its action

An autoregulatory loop controls the expression of the transcription factor NF-Y

The heterotrimeric NF-Y complex is a pioneer factor that binds to CCAAT-genes and regulates their transcription. NF-Y cooperates with multiple transcription factors and co-regulators in order to positively or negatively influence gene transcription. The recruitment of NF-Y to CCAAT box is significantly enriched in cancer-associated gene promoters loci and positively correlates with malignancy. NF-Y subunits, in particular the DNA-binding subunit NF-YA and the histone-fold subunit NF-YC, appear overexpressed in specific types of cancer. Here we demonstrate that NF-Y subunits expression is finely regulated through transcriptional and post-translational mechanisms thus allowing control over basal expression levels. NF-Y negatively regulates the transcription of the genes encoding for its subunits. DNA pull-down/affinity purification assay coupled with Mass Spectrometry identified putative co-regulators, such as Lamin A, involved in NF-YA gene transcription level. We also evidentiate how the stability of the complex is severely affected by the absence of one subunit. Our results identified for the first time one of the mechanisms responsible for NF-Y expression, which may be involved in the aberrant expression and activity observed in tumor cells and other pathological conditions

Disease-induced neuroinflammation and depression

Progression of major depression, a multifactorial disorder with a neuroinflammatory signature, seems to be associated with the disruption of body allostasis. High rates of comorbidity between depression and specific medical disorders, such as, stroke, chronic pain conditions, diabetes mellitus, and human immunodeficiency virus (HIV) infection, have been extensively reported. In this review, we discuss how these medical disorders may predispose an individual to develop depression by examining the impact of these disorders on some hallmarks of neuroinflammation known to be impaired in depressed patients: altered permeability of the blood brain barrier, immune cells infiltration, activated microglia, increased cytokines production, and the role of inflammasomes. In all four pathologies, blood brain barrier integrity was altered, allowing the infiltration of peripheral factors, known to activate resident microglia. Evidence indicated morphological changes in the glial population, increased levels of circulating pro-inflammatory cytokines or increased production of these mediators within the brain, all fundamental in neuroinflammation, for the four medical disorders considered. Moreover, activity of the kynurenine pathway appeared to be enhanced. With respect to the inflammasome NLRP3, a new target whose role in neuroinflammation is emerging as being important, accumulating data suggest its involvement in the pathogenesis of brain injury following stroke, chronic pain conditions, diabetes mellitus or in HIV associated immune impairment. Finally, data gathered over the last 10 years, indicate and confirm that depression, stroke, chronic pain, diabetes, and HIV infection share a combination of underlying molecular, cellular and network mechanisms leading to a general increase in the neuroinflammatory burden for the individual

The transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle

Satellite cells represent myogenic stem cells that allow the homeostasis and repair of adult skeletal muscle. Here the authors report that the transcription factor NF-Y is expressed in satellite cells and is important for their maintenance and proper myogenic differentiation

Alternative splicing of NF-YA promotes prostate cancer aggressiveness and represents a new molecular marker for clinical stratification of patients

Approaches based on expression signatures of prostate cancer (PCa) have been proposed to predict patient outcomes and response to treatments. The transcription factor NF-Y participates to the progression from benign epithelium to both localized and metastatic PCa and is associated with aggressive transcriptional profile. The gene encoding for NF-YA, the DNA-binding subunit of NF-Y, produces two alternatively spliced transcripts, NF-YAs and NF-YAl. Bioinformatic analyses pointed at NF-YA splicing as a key transcriptional signature to discriminate between different tumor molecular subtypes. In this study, we aimed to determine the pathophysiological role of NF-YA splice variants in PCa and their association with aggressive subtypes

In Vitro Cell Culture of Rhus coriaria L.: A Standardized Phytocomplex Rich of Gallic Acid Derivatives with Antioxidant and Skin Repair Activity

This study focused on the biological evaluation and chemical characterization of a new ingredient obtained by in vitro cell culture of Rhus coriaria L. An in vitro plant cell culture method permits to cultivate plant in a short period of time and to obtain extract with a high safety profile for the consumer, free from heavy metals, pesticides, aflatoxins, bacterial or fungal contamination. Through the selection of specific cell culture media, it was possible to obtain a Rhus coriaria cell line with a high content of gallic acid derivatives. The Rhus coriaria L. phytocomplex (RC-P), containing 7.6% w/w of acid gallic derivatives, was obtained by drying of plant cell biomass after 14 days of growth in the final selected culture medium. UPLC-ESI-MS and UPLC-DAD analysis allowed to identify numerous gallic acid derivatives, such as galloyl hexose, trigalloyl hexose and high molecular weight galloyl derivatives, and to quantify their overall content. The antioxidant activity of the RC-P was tested by DPPH assay and the wound healing activity was evaluated using a scratch wound healing test on human keratinocytes and fibroblasts. This work showed that RC-P could be a new effective cosmetic ingredient with antioxidant and skin repair activity

The transcription factor NF-Y is required for satellite stem cell proliferation and skeletal muscle tissue repair

The transcription factor NF-Y, composed by NF-YA, NF-YB and NF-YC subunits, has an important role in the regulation of cellular proliferation and differentiation in different cell types, among which muscle cells. While NF-YA, the DNA binding subunit of NF-Y, is down-regulated in the adult muscle of WT mice, its expression is observed in the mdx mouse, model for Duchenne Muscular Dystrophy, in which a massive regeneration mediated by resident muscle stem cells, namely Satellite Cells (SCs), occurs. With the aim to investigate the role of NF-YA in the SCs proliferation and differentiation, we generated and characterized a conditional knock out mouse model in which NF-YA is deleted in Pax7+ SCs by Tamoxifen induction in adult NF-YAflox/flox:Pax7CreER mice (NF-YA cKO). Cellular and molecular analysis carried out on isolated myofibers and SCs from WT and NF-YA cKO mice highlighted that NF-Y activity is important for the maintenance of SCs homeostasis. NF-YA loss depletes Pax7+ SCs pool and impairs SCs proliferation. Moreover, SCs-mediated regeneration following muscle damage induced by cardiotoxin is delayed in NF-YA cKO. The effect of NF-YA abrogation was also explored in post-natal muscle growth. Immunohistological analysis showed defects in muscle morphology and a decrease in SCs number in 3 weeks aged NF-YA cKO mice, period of major increment of muscle mass  by SCs-mediated myonuclear accretion.  The molecular mechanism underlying the impairment of SCs activity following NF-YA loss was investigated by AdenoCre-induced NF-YA deletion in ex vivo cultured SCs.   Overall, our results highlight a role of NF-Y in muscle regeneration and in SCs fate, whose modulation could be useful to improve stem cell based therapies to treat muscular dystrophies