Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and have a wide range of molecular functions. Given the wide variety of zinc-finger domains, ZNFs are able to interact with DNA, RNA, PAR (poly-ADP-ribose) and other proteins. Thus, ZNFs are involved in the regulation of several cellular processes. In fact, ZNFs are implicated in transcriptional regulation, ubiquitin-mediated protein degradation, signal transduction, actin targeting, DNA repair, cell migration, and numerous other processes. The aim of this review is to provide a comprehensive summary of the current state of knowledge of this class of proteins. Firstly, we describe the actual classification of ZNFs, their structure and functions. Secondly, we focus on the biological role of ZNFs in the development of organisms under normal physiological and pathological conditions.

/pdf/zinc-finger-proteins-in-health-and-disease-gjp0ekik4b.pdf

Zinc-finger proteins in health and disease.

Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.

Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations

Obesity symbolizes a major public health problem. Overweight and obesity are associated to the occurrence of the metabolic syndrome and to adipose tissue dysfunction. The adipose tissue is metabolically active and an endocrine organ, whose dysregulation causes a low-grade inflammatory state and ectopic fat depositions. The Mediterranean Diet represents a possible therapy for metabolic syndrome, preventing adiposopathy or "sick fat" formation.The Mediterranean Diet exerts protective effects in elderly subjects with and without baseline of chronic diseases. Recent studies have demonstrated a relationship between cancer and obesity. In the US, diet represents amount 30-35% of death causes related to cancer. Currently, the cancer is the second cause of death after cardiovascular diseases worldwide. Furthermore, populations living in the Mediterranean area have a decreased incidence of cancer compared with populations living in Northern Europe or the US, likely due to healthier dietary habits. The bioactive food components have a potential preventive action on cancer. The aims of this review are to evaluate the impact of Mediterranean Diet on onset, progression and regression of metabolic syndrome, cancer and on longevity.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13553&path%5B%5D=51221

Impact of Mediterranean diet on metabolic syndrome, cancer and longevity

The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer1-3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

SP and KLF Transcription Factors in Digestive Physiology and Diseases

Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-βR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-βR2 expression and activating the TGF-βR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-βR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC.

ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma.

Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.

/pdf/znf32-protects-against-oxidative-stress-induced-apoptosis-by-3io08sw9li.pdf

ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.

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ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma.

ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.