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  1. Fulltext Deciphering the roles of aryl hydrocarbon receptor (AHR) in regulating carcinogenesis
    Chong ZX, Yong CY, Ong AHK, Yeap SK, Ho WY
    Toxicology, 2023 Aug 15;495:153596.
    PMID: 37480978 DOI: 10.1016/j.tox.2023.153596
    Aryl hydrocarbon receptor (AHR) is a ligand-dependent receptor that belongs to the superfamily of basic helix-loop-helix (bHLH) transcription factors. The activation of the canonical AHR signaling pathway is known to induce the expression of cytochrome P450 enzymes, facilitating the detoxification metabolism in the human body. Additionally, AHR could interact with various signaling pathways such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1α (HIF-1α), nuclear factor ekappa B (NF-κβ), estrogen receptor (ER), and androgen receptor (AR) signaling pathways. Over the past 30 years, several studies have reported that various chemical, physical, or biological agents, such as tobacco, hydrocarbon compounds, industrial and agricultural chemical wastes, drugs, UV, viruses, and other toxins, could affect AHR expression or activity, promoting cancer development. Thus, it is valuable to overview how these factors regulate AHR-mediated carcinogenesis. Current findings have reported that many compounds could act as AHR ligands to drive the expressions of AHR-target genes, such as CYP1A1, CYP1B1, MMPs, and AXL, and other targets that exert a pro-proliferation or anti-apoptotic effect, like XIAP. Furthermore, some other physical and chemical agents, such as UV and 3-methylcholanthrene, could promote AHR signaling activities, increasing the signaling activities of a few oncogenic pathways, such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Understanding how various factors regulate AHR-mediated carcinogenesis processes helps clinicians and scientists plan personalized therapeutic strategies to improve anti-cancer treatment efficacy. As many studies that have reported the roles of AHR in regulating carcinogenesis are preclinical or observational clinical studies that did not explore the detailed mechanisms of how different chemical, physical, or biological agents promote AHR-mediated carcinogenesis processes, future studies should focus on conducting large-scale and functional studies to unravel the underlying mechanism of how AHR interacts with different factors in regulating carcinogenesis processes.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/metabolism
  2. Fulltext Physicochemical and structural properties of Asian Swamp Eel (Monopterus albus) skin gelatin as compared to bovine gelatin
    Rosli, N., Sarbon, N.M.
    International Food Research Journal, 2015;22(2):699-706.
    MyJurnal
    The aims of this study are to report on the extraction and characterization of Asian swamp eel (Monopterus albus) skin gelatin. The characterization conducted were includes chemical composition, pH, gel strength, viscosity, thermal property, color and structure determination of extracted eel skin gelatin. Eel skin contains 70.28% moisture, 11.07% protein, 4.21% fat, and 5.01% ash. The chemical composition of eel skin gelatin (yield of 12.75%) was 18.8% moisture, 67.64% protein, 0.34% fat and 1.08% ash, with a pH of 4.62 and gel strength of 215.96 g (± 9.62 g). Although viscosity (2.8 cPa/min) profile of eel skin gelatin showed lower than that of bovine gelatin, the higher melting temperature (35 °C) of eel skin gelatin indicating its higher stability than bovine gelatin with FTIR spectrum similar to that of typical bovine gelatin. Eel skin gelatin has a 71.4 (± 1.14), a +3.2 (± 0.29), and a +7.52 (± 0.29) for L*, a* and b* value respectively, indicate a darker and less yellow colour. These findings show promising potential for the application of eel skin gelatin as an alternative to commercial gelatin.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
  3. Fulltext NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis
    Rodrigues P, Patel SA, Harewood L, Olan I, Vojtasova E, Syafruddin SE, et al.
    Cancer Discov, 2018 Jul;8(7):850-865.
    PMID: 29875134 DOI: 10.1158/2159-8290.CD-17-1211
    Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states.Significance: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 850-65. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics*
  4. Cyp2a5 Promoter-based Gene Reporter Assay: A Novel Design of Cell-based Bioassay for Toxicity Prediction
    Abu-Bakar A, Hu H, Lang MA
    Basic Clin Pharmacol Toxicol, 2018 Sep;123 Suppl 5:72-80.
    PMID: 29788535 DOI: 10.1111/bcpt.13046
    The murine cytochrome P450 2a5 (Cyp2a5) gene is regulated by complex interactions of various stress-activated transcription factors (TFs). Elevated Cyp2a5 transcription under chemical-induced stress conditions is achieved by interplay between the various TFs - including as aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2) - at the 'stress-responding' cluster of response elements on the Cyp2a5 promoter, as well as through mRNA stabilization mediated by interaction of the stress-activated heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) with the 3'-UTR of the CYP2A5 mRNA. We designed a unique toxicity pathway-based reporter assay to include regulatory regions from both the 5' and the 3' untranslated regions of Cyp2a5 in a luciferase reporter plasmid to reflect in vivo responses to chemical insult. Human breast cancer MCF-7 cells were stably transfected with pGL4.38-Cyp2a5_Wt3k (wild-type) or mutant - pGL4.38-Cyp2a5_StREMut and pGL4.38-Cyp2a5_XREMut - reporter gene to monitor chemical-induced cellular response mediated by AhR and Nrf2 signalling. The recombinant cells were treated with representative of AhR agonist, polycyclic aromatic hydrocarbons, brominated flame retardant, fluorosurfactant, aromatic organic compound and metal, to determine the sensitivity of the Cyp2a5 promoter-based gene reporter assays to chemical insults by measuring the LC50 and EC50 of the respective chemicals. The three assays are sensitive to sublethal cellular responses of chemicals, which is an ideal feature for toxicity pathway-based bioassay for toxicity prediction. The wild-type reporter responded well to chemicals that activate crosstalk between the AhR and Nrf2, whilst the mutant reporters effectively gauge cellular response driven by either Nrf2/StRE or AhR/XRE signalling. Thus, the three gene reporter assays could be used tandemly to determine the predominant toxicity pathway of a given compound.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/metabolism
  5. Fulltext Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model
    Garza-Manero S, Sindi AAA, Mohan G, Rehbini O, Jeantet VHM, Bailo M, et al.
    Epigenetics Chromatin, 2019 12 12;12(1):73.
    PMID: 31831052 DOI: 10.1186/s13072-019-0320-7
    BACKGROUND: Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells.

    RESULTS: We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2.

    CONCLUSIONS: We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/metabolism; Basic Helix-Loop-Helix Transcription Factors/chemistry
  6. Fulltext The oncolytic activity of Newcastle disease virus in clear cell renal carcinoma cells in normoxic and hypoxic conditions: the interplay between von Hippel-Lindau and interferon-β signaling
    Ch'ng WC, Stanbridge EJ, Yusoff K, Shafee N
    J Interferon Cytokine Res, 2013 Jul;33(7):346-54.
    PMID: 23506478 DOI: 10.1089/jir.2012.0095
    Viral-mediated oncolysis is a promising cancer therapeutic approach offering an increased efficacy with less toxicity than the current therapies. The complexity of solid tumor microenvironments includes regions of hypoxia. In these regions, the transcription factor, hypoxia inducible factor (HIF), is active and regulates expression of many genes that contribute to aggressive malignancy, radio-, and chemo-resistance. To investigate the oncolytic efficacy of a highly virulent (velogenic) Newcastle disease virus (NDV) in the presence or absence of HIF-2α, renal cell carcinoma (RCC) cell lines with defective or reconstituted wild-type (wt) von Hippel-Lindau (VHL) activity were used. We show that these RCC cells responded to NDV by producing only interferon (IFN)-β, but not IFN-α, and are associated with increased STAT1 phosphorylation. Restoration of wt VHL expression enhanced NDV-induced IFN-β production, leading to prolonged STAT1 phosphorylation and increased cell death. Hypoxia augmented NDV oncolytic activity regardless of the cells' HIF-2α levels. These results highlight the potential of oncolytic NDV as a potent therapeutic agent in the killing of hypoxic cancer cells.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/metabolism
  7. Fulltext A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
    Lou H, Lu Y, Lu D, Fu R, Wang X, Feng Q, et al.
    Am J Hum Genet, 2015 Jul 02;97(1):54-66.
    PMID: 26073780 DOI: 10.1016/j.ajhg.2015.05.005
    Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics*
  8. Fulltext Endogenous HIF2A reporter systems for high-throughput functional screening
    Zaini MN, Patel SA, Syafruddin SE, Rodrigues P, Vanharanta S
    Sci Rep, 2018 08 13;8(1):12063.
    PMID: 30104738 DOI: 10.1038/s41598-018-30499-2
    Tissue-specific transcriptional programs control most biological phenotypes, including disease states such as cancer. However, the molecular details underlying transcriptional specificity is largely unknown, hindering the development of therapeutic approaches. Here, we describe novel experimental reporter systems that allow interrogation of the endogenous expression of HIF2A, a critical driver of renal oncogenesis. Using a focused CRISPR-Cas9 library targeting chromatin regulators, we provide evidence that these reporter systems are compatible with high-throughput screening. Our data also suggests redundancy in the control of cancer type-specific transcriptional traits. Reporter systems such as those described here could facilitate large-scale mechanistic dissection of transcriptional programmes underlying cancer phenotypes, thus paving the way for novel therapeutic approaches.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors/genetics*
  9. microRNA-548m suppresses cell migration and invasion by targeting aryl hydrocarbon receptor in breast cancer cells
    Nor WMFSBW, Chung I, Said NABM
    Oncol Res, 2020 Oct 27.
    PMID: 33109304 DOI: 10.3727/096504020X16037933185170
    Breast cancer is the most commonly diagnosed cancer among women and one of the leading causes of cancer mortality worldwide, in which the most severe form happens when it metastasizes to other regions of the body. Metastasis is responsible for most treatment failures in advanced breast cancer. Epithelial-mesenchymal transition (EMT) plays a significant role in promoting metastatic processes in breast cancer. MicroRNAs (miRNAs) are highly conserved endogenous short non-coding RNAs that play a role in regulating a broad range of biological processes, including cancer initiation and development, by functioning as tumor promoters or tumor suppressors. Expression of miR-548m has been found in various types of cancers, but the biological function and molecular mechanisms of miR-548m in cancers have not been fully studied. Here, we demonstrated the role of miR-548m in modulating EMT in the breast cancer cell lines MDA-MB-231 and MCF-7. Expression data for primary breast cancer obtained from NCBI GEO datasets showed that miR-548m expression was downregulated in breast cancer patients compared with healthy group. We hypothesize that miR-548m acts as a tumor suppressor in breast cancer. Overexpression of miR-548m in both cell lines increased E-cadherin expression and decreased the EMT-associated transcription factors SNAI1, SNAI2, ZEB1 and ZEB2, as well as MMP9 expression. Consequently, migration and invasion capabilities of both MDA-MB-231 and MCF-7 cells were significantly inhibited in miR-548m-overexpressing cells. Analysis of 1059 putative target genes of miR-548m revealed common pathways involving both tight junction and the mTOR signaling pathway, which has potential impacts on cell migration and invasion. Furthermore, this study identified aryl hydrocarbon receptor (AHR) as a direct target of miR-548m in breast cancer cells. Taken together, our findings suggest a novel function of miR-548m in reversing the EMT of breast cancer by reducing their migratory and invasive potentials, at least in part via targeting AHR expression.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
  10. Penghasilan Sirap Glukosa Berfruktosa Tinggi dari Kanji Ubi Keledek Msp94 (Production of High Fructose Glucose Syrup from Sweet Potato MSP94 Starch)
    Hasnah Haron, Osman Hassan, Mamot Said
    Sains Malaysiana, 2005;34.
    This study comprised of physicochemical characterizations of starch extracted from Msp94 sweet potato tuber and production of high fructose glucose syrup from the starch. Msp94 sweet potato starch consisted of 7.3% water, 0.2% protein, 0.4% fat, 1.3% total ash, 94.8% total carbohydrates, 83.0% starch and 20.6% apparent amylose. The starch granules were spherical, polygonal and irregular in shapes with the size of 13-14 mm. Enzymatic hydrolysis of Msp94 sweet potato starch for 24,48, 72 hours, using a mixture of amyglucosidase-pullulanase enzymes during saccharification process, produced starch hydrolysates with dextrose equivalent (DE) of 94.8, 99.1, 99.3 respectively. This is followed by reduction in viscosity of the starch hydrolysates. Conversion of the Msp94 starch to percent of glucose after hydrolysing for 24,48 and 72 hours were 97.1%, 109.5% and 103.2%, respectively. Msp94 starch hydrolysates was then purified using three types of ion exchange resins and isomerized to highfructose syrup using glucose isomerase enzyme (Sweetzyme T). Thefructose content in isomerized Msp94 syrup was (43.8-46.5%) was comparable to the fructose content (44%) in commercial High Fructose Corn Syrup (HFCS) 42.
    [Kajian ini merangkumi pencirian fizikokimia kanji yang diekstrak daripada ubi keledek Msp94 dan penghasilan sirap glukosa berfruktosa tinggi daripada kanji ini. Kanji ubi keledek Msp94 mengandungi 7.3% air, 0.2% protein, 0.4% lemak, 1.3% abu total, 94.8% karbohidrat total, 83.0% kanji dan 20.6% amilosa ketara. Purata saiz granul kanji adalah 13-14 mm, berbentuk bulat, poligon dan bentuk yang tidak tetap. Hidrolisis berenzim menggunakan gabungan enzim glukoamilase-pululanase dalam proses sakarifikasi, yang dijalankan ke atas kanji ubi keledek Msp94 selama 24, 48, 72 jam menghasilkan hidrolisat kanji dengan setaraan dekstrosa (DE) masing-masing pada 94.8, 99.1, 99.3. 1ni diikuti dengan kelikatan hidrolisat kanji yang semakin menurun. Penukaran kanji Msp94 kepada peratus glukosa adalah sebanyak 97.1 %, 109.5% dan 103.2% setelah dihidrolisis selama 24,48 dan 72 jam. Hidrolisat kanji Msp94 ditulenkan menggunakan tiga jenis resin penukar ion dan diisomer kepada sirap berfruktosa tinggi menggunakan enzim glukosa isomerase (Sweetzyme T). Kandungan fruktosa (43.8-46.5%) dalam sirap Msp94 yang telah diisomer adalah setara dengan kandunganfruktosa (44%) dalam sirap komersial, High Fructose Corn Syrup (HFCS) 42].
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
  11. Bortezomib attenuates HIF-1- but not HIF-2-mediated transcriptional activation
    Abd-Aziz N, Stanbridge EJ, Shafee N
    Oncol Lett, 2015 Oct;10(4):2192-2196.
    PMID: 26622817
    Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism for its action is that it prevents the proteasomal degradation of proapoptotic proteins, leading to enhanced apoptosis. Although the α subunit of hypoxia-inducible factor (HIF)-1 is not degraded with bortezomib treatment, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for the survival of hypoxic tumor cells. The majority of reports have focused on the effects of bortezomib on the transcriptional activities of HIF-1, but not HIF-2. The present study investigated the effects of bortezomib on HIF-2 activity in cancer cells with different levels of HIF-1α and HIF-2α subunits. HIF-α subunit levels were detected using specific antibodies, while HIF transcriptional activities were evaluated using immunodetection, reverse transcription-polymerase chain reaction and luciferase reporter assay. Bortezomib treatment was found to suppress the transcription and expression of CA9, a HIF-1-specific target gene; however, it had minimal effects on EPO and GLUT-1, which are target genes of both HIF-1 and HIF-2. These data suggest that bortezomib attenuates the transcriptional activity only of HIF-1, and not HIF-2. This novel finding on the lack of an inhibitory effect of bortezomib on HIF-2 transcriptional activity has implications for the improvement of design and treatment modalities of bortezomib and other PI drugs.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
  12. Fulltext Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
    Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G, Wu T, et al.
    Nat Commun, 2021 08 17;12(1):4997.
    PMID: 34404774 DOI: 10.1038/s41467-021-24921-z
    Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
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