Micronutrients Importance in Cancer Prevention-Minerals.

Cancer, a non-communicable disease with diverse kinds is one of the major global problems with high incidence and no proven method to prevent or treat. Minerals including trace elements are significant micronutrients for preserving the body's typical physiological function. In contrast to extremely processed industrial food, they are rich in natural sources of food and frequently included in nutritional supplements. The daily intake, storage capacities, and homeostasis of micronutrients depend on specific dietary practices in contemporary civilization and can be disturbed by various malignancies. Varied minerals have different effects on the status of cancer depending on how they affect these pathways. The outcomes could differ depending on the mineral such as calcium's supply and the cancer's location. A mineral called zinc helps the immune system function better and aids in wound healing. On the other hand, selenium exhibits anti-oxidant functions and has a dose-response relationship with many cancer types. However, this component can make the patient's condition worse. Although the body produces free radicals when iron is deficient, anaemia affects a patient's quality of life and ability to receive therapy. This chapter compiles the knowledge of minerals connected to unusual accumulation or depletion states in various malignancies.

Effects of Phoenix dactylifera against Streptozotocin-Aluminium Chloride Induced Alzheimer's Rats and Their In Silico Study.

Phoenix dactylifera is known for medicinal importance due to its antioxidant, antidiabetic, antidepressant, and anti-inflammatory properties. This study is aimed at evaluating the effect of P. dactylifera seeds to cure Alzheimer's disease (AD). AD was induced in the rats with streptozotocin + aluminium chloride followed by treatment of methanolic extract of P. dactylifera seeds. The blood glucose levels were determined at regular intervals, which showed a prominent decrease in the extracts treated group. Behavior tests, including the Elevated Plus Maze (EPM) test and Morris Water Maze (MWM) test, were used to evaluate memory patterns in rats. The results indicated that extract-treated rats significantly improved memory behavior compared to the diseased group. After dissection, the serum electrolytes, antioxidant enzymes, and choline esterase enzymes were measured in different organs. The serum parameters creatinine, urea, and bilirubin increased after extract treatment. Similarly, the level of antioxidant enzymes like peroxidases (POD), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and thiobarbituric acid reactive substance (TBARS) in the extract-treated group showed improved results that were close to the normal control group. The enzyme (lipase, insulin, amylase, and acetylcholine) levels were found enhanced in extract groups as compared to diseased rats. High-performance liquid chromatography (HPLC) was used to determine the level of dopamine and serotonin neurotransmitters, which were increased significantly for P. dactylifera seeds with values of 0.18 µg/mg tissue and 0.56 µg/mg tissue, respectively. Overall, results showed that P. dactylifera seeds proved to be quite efficient in improving the memory and behavior of treated rats. The antioxidants and enzymes were also increased; therefore, it may be a potential candidate for treating AD.

Vitamin B6 based Pt(II) complexes: biomolecule derived potential cytotoxic agents for thyroid cancer.

Vitamin B6 is an essential vitamin that serves as a co-enzyme in a number of enzymatic reactions in metabolism of lipids, amino acids, and glucose. In the current study, we synthesized vitamin B6 derived ligand (L) and its complex Pt(L)Cl (C1). The ancillary chloride ligand of C1 was exchanged with pyridine co-ligand and another complex Pt(L)(py).BF4 (C2) was obtained. Both these complexes were obtained in excellent isolated yields and characterized thoroughly by different analytical methods. Thyroid cancer is one of the most common malignancies of the endocrine system, we studied the in vitro anticancer activity and mechanism of these vitamin B6 derived L and Pt(II) complexes in thyroid cancer cell line (FTC). Based on MTT assay, cell proliferation rate was reduced in a dose-dependent manner. According to apoptosis analysis, vitamin B6 based Pt(II) complexes treated cells depicted necrotic effect and TUNEL based apoptosis was observed in cancer cells. Furthermore, qRT-PCR analyses of cancer cells treated with C1 and/or C2 showed regulated expression of anti-apoptotic, pro-apoptosis and autophagy related genes. Western blot results demonstrated that C1 and C2 induced the activation of p53 and the cleavage of Poly (ADP-ribose) polymerase (PARP). These results suggest that these complexes inhibit the growth of FTC cells and induce apoptosis through p53 signaling. Thus, vitamin B6 derived Pt(II) complexes C1 and C2 may be potential cytotoxic agents for the treatment of thyroid cancer.

Antibacterial, Antihemolytic, Cytotoxic, Anticancer, and Antileishmanial Effects of Ajuga bracteosa Transgenic Plants.

Herbal and traditional medicines can play a pivotal role in combating cancer and neglected tropical diseases. Ajuga bracteosa, family Lamiaceae, is an important medicinal plant. The genetic transformation of A. bracteosa with rol genes of Agrobacterium rhizogenes further enhances its metabolic content. This study aimed at undertaking the molecular, phytochemical, and in vitro biological analysis of A. bracteosa extracts. We transformed the A. bracteosa plant with rol genes and raised the regenerants from the hairy roots. Transgenic integration and expression of rolB were confirmed by conventional polymerase chain reaction (PCR) and qPCR analysis. The methanol: chloroform crude extracts of wild-type plants and transgenic regenerants were screened for in vitro antibacterial, antihemolytic, cytotoxic, anticancer, and leishmanial activity. Among all plants, transgenic line 3 (ABRL3) showed the highest expression of the rolB gene. Fourier transform infra-red (FTIR) analysis confirmed the enhanced number of functional groups of active compounds in all transgenic lines. Moreover, ABRL3 exhibited the highest antibacterial activity, minimum hemolytic activity (CC50 = 7293.05 ± 7 µg/mL) and maximum antileishmanial activity (IC50 of 56.16 ± 2 µg/mL). ABRL1 demonstrated the most prominent brine shrimp cytotoxicity (LD5039.6 ± 4 µg/mL). ABRL3 was most effective against various human cancer cell lines with an IC50 of 57.1 ± 2.2 µg/mL, 46.2 ± 1.1 µg/mL, 72.4 ± 1.3 µg/mL, 73.3 ± 2.1 µg/mL, 98.7 ± 1.6 µg/mL, and 97.1 ± 2.5 µg/mL against HepG2, LM3, A549, HT29, MCF-7, and MDA-MB-231, respectively. Overall, these transgenic extracts may offer a cheaper therapeutic source than the more expensive synthetic drugs.

Transcriptome analysis reveals the encystment-related lncRNA expression profile and coexpressed mRNAs in Pseudourostyla cristata.

Ciliated protozoans form dormant cysts for survival under adverse conditions. The molecular mechanisms regulating this process are critical for understanding how single-celled eukaryotes adapt to the environment. Despite the accumulated data on morphology and gene coding sequences, the molecular mechanism by which lncRNAs regulate ciliate encystment remains unknown. Here, we first detected and analyzed the lncRNA expression profile and coexpressed mRNAs in dormant cysts versus vegetative cells in the hypotrich ciliate Pseudourostyla cristata by high-throughput sequencing and qRT-PCR. A total of 853 differentially expressed lncRNAs were identified. Compared to vegetative cells, 439 and 414 lncRNAs were upregulated and downregulated, respectively, while 47 lncRNAs were specifically expressed in dormant cysts. A lncRNA-mRNA coexpression network was constructed, and the possible roles of lncRNAs were screened. Three of the identified lncRNAs, DN12058, DN20924 and DN30855, were found to play roles in fostering encystment via their coexpressed mRNAs. These lncRNAs can regulate a variety of physiological activities that are essential for encystment, including autophagy, protein degradation, the intracellular calcium concentration, microtubule-associated dynein and microtubule interactions, and cell proliferation inhibition. These findings provide the first insight into the potentially functional lncRNAs and their coexpressed mRNAs involved in the dormancy of ciliated protozoa and contribute new evidence for understanding the molecular mechanisms regulating encystment.

The Encystment-Related MicroRNAs and Its Regulation Molecular Mechanism in Pseudourostyla cristata Revealed by High Throughput Small RNA Sequencing.

MicroRNAs (miRNAs) regulate the expression of target genes in diverse cellular processes and play important roles in different physiological processes. However, little is known about the microRNAome (miRNAome) during encystment of ciliated protozoa. In the current study, we first investigated the differentially expressed miRNAs and relative signaling pathways participating in the transformation of vegetative cells into dormant cysts of Pseudourostyla cristata (P. cristata). A total of 1608 known miRNAs were found in the two libraries. There were 165 miRNAs with 1217 target miRNAs. The total number of differential miRNAs screened between vegetative cells and dormant cysts databases were 449 with p < 0.05 and |log2 fold changes| > 1. Among them, the upregulated and downregulated miRNAs were 243 and 206, respectively. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that some of the differentially expressed miRNAs were mainly associated with oxidative phosphorylation, two-component system, and biosynthesis of amino acids. Combining with our bioinformatics analyzes, some differentially expressed miRNAs including miR-143, miR-23b-3p, miR-28, and miR-744-5p participates in the encystment of P. cristata. Based on these findings, we propose a hypothetical signaling network of miRNAs regulating or promoting P. cristata encystment. This study shed new lights on the regulatory mechanisms of miRNAs in encystment of ciliated protozoa.

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics.

The encystment of many ciliates is an advanced survival strategy against adversity and the most important reason for ciliates existence worldwide. However, the molecular mechanism for the encystment of free-living ciliates is poorly understood. Here, we performed comparative transcriptomic analysis of dormant cysts and trophonts from Pseudourostyla cristata using transcriptomics, qRT-PCR and bioinformatic techniques. We identified 2565 differentially expressed unigenes between the dormant cysts and the trophonts. The total number of differentially expressed genes in GO database was 1752. The differential unigenes noted to the GO terms were 1993. These differential categories were mainly related to polyamine transport, pectin decomposition, cytoplasmic translation, ribosome, respiratory chain, ribosome structure, ion channel activity, and RNA ligation. A total of 224 different pathways were mapped. Among them, 184 pathways were upregulated, while 162 were downregulated. Further investigation showed that the calcium and AMPK signaling pathway had important induction effects on the encystment. In addition, FOXO and ubiquitin-mediated proteolysis signaling pathway jointly regulated the encystment. Based on these findings, we propose a hypothetical signaling network that regulates Pseudourostyla cristata encystment. Overall, these results provide deeper insights into the molecular mechanisms of ciliates encystment and adaptation to adverse environments.

REGγ potentiates TGF-ß/Smad signal dependent epithelial-mesenchymal transition in thyroid cancer cells.

Thyroid cancer is the most common endocrine cancer with an increasing incidence and mortality. Epithelial-mesenchymal transition (EMT) is a biological process contributing to tumor progression, metastasis, and the acquisition of chemotherapy resistance. The impact of the REGγ proteasome activator on EMT in human thyroid cancer cells and the molecular mechanism is still unclear. Here, we found silencing REGγ in thyroid cancer cells inhibited cell migration and invasion, with concurrent upregulation of E-cadherin and Smurf2 expression. Mechanistically, REGγ dependent regulation of Smurf2, an E3 ligase for Smad3, contributed to alteration of Zeb1/2, Snail, Slug, and Twist. Consistently, TGF-ß mediated suppression of E-cadherin was attenuated in REGγ deficient cells, coupled with changes in cell morphology, migration and invasion. Furthermore, xenograft metastasis mouse model showed a reduced E-cadherin expression at both mRNA and protein levels, and decreased cell migration. Taken together, our findings provided an important evidence for the role of REGγ in tumor suppression, thereby implicating REGγ as a potential anti-cancer strategy in thyroid cancer therapy.

Anticancer activity and mechanism of bis-pyrimidine based dimetallic Ru(II)(η6-p-cymene) complex in human non-small cell lung cancer via p53-dependent pathway.

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide, which is related with poor prognosis and resistance to chemotherapy. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy. In the present study, we synthesized a novel bis-pyrimidine based ligand 1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene (L) and used it in the synthesis of a dimetallic Ru(II) cymene complex [(Ru(η6-p-cymene)Cl)2(1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene)] (L-Ru). We checked the stability of this complex in solution state in D2O/DMSO­d6 mixture and found it to be highly stable under these conditions. We determined the anticancer activity and mechanism of action of L-Ru in human NSCLC A549 and A427 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and related biological analyses. These results revealed that L-Ru exerted a strong inhibitory effect on the cells proliferation,G0/G1-arrest, accompanied with upregulation of p53, p21, p15, cleaved Poly (ADP-ribose) polymerase (PARP) protein and downregulation of cell cycle markers. L-Ru inhibited cell migration and invasion. The mitochondria-mediated apoptosis of NSCLC induced by L-Ru was also observed followed by the increase of apoptosis regulator B-cell lymphoma 2 associated X (BAX), and activation of caspase-3/-9. The effects of L-Ru on the cell viability, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and Annexin V-positive cells apoptosis induction were remarkably attenuated. This complex induced DNA damage, cell cycle arrest and cell death via caspase-dependent apoptosis involving PARP activation and induction of p53-dependent pathway. These findings suggested that this ruthenium complex might be a potential effective chemotherapeutic agent in NSCLC therapy.

ONS-donor ligand based Pt(II) complexes display extremely high anticancer potency through autophagic cell death pathway.

The current study unveils ONS-donor ligand based Pt(II) complexes with unusual anticancer potency showing higher anticancer effect as compared to cisplatin. This series of Pt(II)(R-salicylaldimine)Cl (C1a-C4a) (R = 5-H, 5-CH3, F, 3-CH3O) complexes were prepared in single step in good isolated yields from commercially available materials. The chloride ancillary ligand of "a" series (C1a-C4a) was replaced with 4-picoline and "b" series of four complexes Pt(II)(R-salicylaldimine)(4-picoline)BF4 (C1b-C4b) (R = 5-H, 5-CH3, F, 3-CH3O) was obtained. All these complexes were characterized by different structure elucidation techniques. Among these, the structures of C1a, C2a, C2b and C3b were determined in solid state by single crystal X-ray analysis. We found quick aquation of "a" series of complexes in DMSO/water mixture that was well investigated by 1H NMNR, LCMS and ESI-MS, while "b" series of these complexes was quite stable over a month as described by the 1H NMNR in DMSO/D2O mixture. This ONS-donor ligand based class of Pt(II) complexes showed unusual anticancer potency in non-small cell lung cancer A549, colorectal cancer HT-29 and triple negative breast cancer MDA-MB-231 cells. These Pt(II) complexes induced PARP cleavage and significantly inhibited colony formation ability of cancer cells. Mechanistically, we found reduced aggressive growth of cancer cells by the induction of autophagic cell death via LC3-I/LC3-II expression and recruitment of LC3B to autophagosomal membrane. These complexes induced p21 expression, that suggested their potentials to suppress cell cycle progression. Significant activation of Caspase3/7-dependent apoptotic signaling was observed in cancer cells treated with these Pt(II) complexes. Morphological changes of cancer cells suggested their potentials to modulate epithelial-mesenchymal-transition (EMT) like features of cancer cells. Gel electrophoresis study revealed their interaction with plasmid DNA. Similarly, strong growth retardation effect and filamentous morphology was observed in Escherichia coli (E. coli). These ONS-donor Pt(II) complexes possessed strong anticancer effect in multiple human cancer cells via activation of multiple pathways for apoptotic and autophagic cell death.

Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling.

A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))2(bis-salicylaldimine)Cl2 (C1C4) were prepared. These complexes were obtained in excellent isolated yields and characterized in detail by using different spectroscopic techniques. The structure of C1 was also determined in solid state by single crystal X-ray analysis. These complexes were studied for their cytotoxic effect against three different types of human cancer cells including hepatocellular carcinoma (HepG2), non-small-cell lung cancer (A549) and breast cancer (MCF-7) cells by MTT assay. These complexes showed considerable cytotoxic effect in all the above-mentioned cell lines that was comparable to the effect of cisplatin. C1 and C2 showed moderate anticancer effect while C3 and C4 showed reasonable cytotoxicity. We found the cytotoxicity was increased in series from C1 to C4 representing the effect of ligand modification from small to bulky group at the amine functionality of the salicylaldimine. We selected C3 and C4 for mechanistic anticancer study in MCF-7 cells. The acridine orange/ethidium bromide and DAPI staining assays of MCF-7 cells treated with Ru(II) complexes showed apoptosis in cancer cells. Similarly, these complexes induced p53 protein expression in MCF-7 cells. Further, increased mRNA levels of p63, p73, PUMA, BAX and NOXA genes were observed in response to the treatment with C3 and C4, while cyclinD1, MMP3 and ID1 gene expression was significantly reduced. We found reduced invasion ability in breast cancer cells treated with C3 and C4. Taken together, we demonstrated that bis-salicylaldimine based dimetallic Ru-(p-cymene) complexes exerts anticancer effects by p53 pathway, suggesting the promising chemotherapeutic potentials of these Ru(II) complexes for the treatment of cancer. This study may further pave for their in depth in vitro or in vivo anticancer investigations.

New contribution to the morphology and molecular mechanism of Euplotes encysticus encystment.

Ciliated protists are a large group of single-cell eukaryotes, leading to the resting cysts in unfavorable environmental condition. However, the underlying molecular mechanism of encystment in the free-living ciliates is poorly understood. Here we show that the resting cysts are better than the vegetative cells of Euplotes encysticus in adverse survivor with respect to energy metabolism. Therefore scale identification of encystment-related proteins in Euplotes encysticus was investigated by iTRAQ analysis. We analyzed a total of 130 proteins, in which 19 proteins involving 12 upregulated and 7 downregulated proteins were associated with encystment in the resting cysts in comparison with the vegetative cells. Moreover, direct fluorescent labeling analysis showed that the vegetative cells treated with shRNA-ß-tubulin recombinant E. coli accumulated a large number of granular materials, and dramatic cell morphology changes. Importantly, the cell membrane rupture phenomenon was observed after three weeks of shRNA-ß-tubulin interference as compared to the control group. These results revealed that different proteins might play an important role in the process of the vegetative cells into the resting cysts. These results will help to reveal the morphological changes and molecular mechanism of resting cyst formation of ciliates.

Homo- and heteroleptic Pt(II) complexes of ONN donor hydrazone and 4-picoline: A synthetic, structural and detailed mechanistic anticancer investigation.

Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect. The overall anticancer effect of all these complexes was higher in liver (HepG2) and lung (H460) cancer cell lines and the effect of C2b and C3b was observed to be the highest among these 10 complexes. Therefore, we selected C2b and C3b to study their in vitro anticancer mechanism in HepG2 and H460 cancer cells. C2b and C3b changed cancer cell morphology and inhibited cell migration. The anticancer mechanistic studies demonstrated that C2b and C3b induced cell apoptosis, as evidenced by DAPI and AO/EB staining and flow cytometry analyses. Moreover, qRT-PCR and western blotting analysis showed that H460 and HepG2 cells treated with C2b and C3b significantly increased the expression of p53, p63, p21, p15, Bax and decreased Bcl-2 and c-Myc levels. The DNA binding property of these complexes was investigated by gel electrophoresis using pBR322 plasmid DNA. Taken together, the results obtained from the present study demonstrated the potentials of this new class of Pt(II) complexes in reduction of cell viability, suppression of cell migration and acceleration of apoptosis in different cancer cells.

REGγ Contributes to Regulation of Hemoglobin and Hemoglobin δ Subunit.

Hemoglobin (Hb) is a family of proteins in red blood cells responsible for oxygen transport and vulnerable for oxidative damage. Hemoglobin δ subunit (HBD), a member of Hb family, is normally expressed by cells of erythroid lineage. Expression of Hb genes has been previously reported in nonerythroid and hematopoietic stem cells. Here, we report that Hb and HBD can be degraded via REGγ proteasome in hemopoietic tissues and nonerythroid cells. For this purpose, bone marrow, liver, and spleen hemopoietic tissues from REGγ+/+ and REGγ-/- mice and stable REGγ knockdown cells were evaluated for the degradation of Hb and HBD via REGγ. Western blot and immunohistochemical analyses exhibited downregulation of Hb in REGγ wild-type mouse tissues. This was validated by dynamic analysis following blockade of de novo synthesis of proteins with CHX. Degradation of HBD only occurred in REGγ WT cells but not in REGγN151Y, a dominant-negative REGγ mutant cell. Notably, downregulation of HBD was found in HeLa shN cells with stimulation of phenylhydrazine, an oxidation inducer, suggesting that the REGγ proteasome may target oxidatively damaged Hbs. In conclusion, our findings provide important implications for the degradation of Hb and HBD in hemopoietic tissues and nonerythroid cells via the REGγ proteasome.

Identification of cyst wall proteins of the hypotrich ciliate Euplotes encysticus using a proteomics approach.

Euplotes encysticus is a species of Hypotrich ciliates, which form cyst wall by secreting the special substances on encounter of adverse environment. It has critical significance to study the component and mechanism underlying resting cyst, during resisting unfavorable conditions in dormancy induction. The present study was aimed to investigate the effects of cyst wall proteins of Euplotes encysticus by using biochemical methods. Therefore, protein extracts were separated by SDSPAGE, identified and analyzed by MALDI-TOF MS and Bioinformatics tools. We detected 42 cyst wall proteins, 26 were functional proteins and 16 proteins consist of unknown function; which is consistent with cyst wall specificity. These results partially revealed the components of resting cyst wall formed after the cells differentiation of Euplotes encysticus. In addition, our data suggested that the function of cyst wall proteins are more likely involved in the mechanical protection, signal transduction, material transport, protein degradation and energy metabolism to survival, with potentially importance implications in the molecular mechanism of eukaryocyte dormancy under stress condition.

Antimicrobial, antitumor and brine shrimp lethality assay of Ranunculus arvensis L. extracts.

To investigate the antitumor activity, brine shrimp lethality assay, antibacterial and antifungal activity of Methanol Extract (ME), Water Extract (WE), Acetone Extract (AE), Chloroform Extract (CE), Methanol-Water Extract (MWE), Methanol-Acetone Extract (MAE), Methanol-Chloroform Extract (MCE) of Ranunculus arvensis (L.). Antitumor activity was evaluated with Agrobacterium tumefaciens (At10) induced potato disc assay. Cytotoxicity was evaluated with brine shrimp lethality assay. Antibacterial activity was evaluated with six bacterial strains including Escherichia coli, Enterobacter aerogenes, Bordetella bronchiseptica, Klebsiella pneumoniae, Micrococcus luteus and Streptococcus anginosus and antifungal screening was done against five fungal strains including Aspergillus niger, A. flavus, A. fumigates, Fusarium solani and Mucor species by using disc diffusion method. Best antitumor activity was obtained with ME and WE, having highest IC50 values 20.27 ± 1.62 and 93.01 ± 1.33µg/disc. Brine shrimp lethality assay showed LC50 values of AE, MAE and ME were obtained as 384.66 ± 9.42µg/ml, 724.11 ± 8.01µg/ml and 978.7 ±8.01 µg/ml respectively. WE of R. arvensis revealed weak antimicrobial result against the tested microorganisms. On the other hand, the antifungal activity of the plant extracts was found to be insignificant. These findings demonstrate that extracts of R. arvensis possesses significant antitumor activity. Further extensive study is necessary to assess the therapeutic potential of the plant.

Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.

Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Krüppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status.