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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another example of a small-molecule transcription factor inhibitor is trabectedin (YondelisTM) which inhibits NF-Y/PCAF. It was approved in 2015 by the FDA for the treatment of two subtypes of soft-tissue sarcomas, liposarcoma, and leiomyosarcoma.
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Although the human genome is designed in a way that important gene functions have a certain redundancy, e.g., by gene families, this is not the case for TP53: the human genome comprises only a single copy of this important gene. Genetic changes in TP53 are therefore of great importance (Bullock and Fersht, 2001) and found in various degrees in all diagnosed tumor types (lung 80–95%; ovary: 90%; head and neck: 70–80%; breast: 15–80%; esophagus: 40–60%; bladder: 50%; colon and brain: 20–60%). Missense mutations in TP53 are mainly found in the DNA binding domain (~95%), and therefore the presence of a single mutated TP53 allele in a cell causes a 75% drop of p53 activity. This is due to the fact that only a p53 tetramer, consisting of four intact p53 proteins, remains functional. In addition, mutant p53 protein is more stable than wild-type p53 protein, and interacts with a large variety of other transcription factors (NF-Y, E2Fs, NFkBp65, NfkBp50, SREBP, YAP, VDR, or NRF2) to steer proliferation, invasion, and metastasis. Binding of mutant p53 to p63 inhibits p63-mediated metastasis suppressor functions (Muller et al., 2014), and mutant p53 can regulate the expression of SHARP1 and Dicer and thus influences a complete network of miRNAs (Wei et al., 2014; Luo et al., 2018).
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Jiang et al. (2013) have developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTLs) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. The authors have found 389,573 and 1,214,416 SNP–transcript–CYP2D6 activity trios that are strongly associated for two different genotype platforms, namely, Affymetrix and Illumina, respectively. In the Affymetrix data set, 295 SNPs correlate with at least 20 genes, which are used to check for overlapping with the results of mediation analysis. A total of 289 eQTL hotspots are found to correlate with 1542 gene expression profiles. The Illumina data set has found that 724 SNPs correlate with at least 20 genes, and 719 of the hotspots are significantly correlated with 2444 genes in mediation analysis. Nine hundred thirty-nine and 1420 genes are successfully mapped in the Ingenuity database for two platforms. The majority of eQTLs are trans-SNPs. Five (CCL16, CCL20, CMTM5, IL-6, and SPP1) and 7 (CCL16, CCL20, CKLF, CKLFSF5, EPO, FAM3C, and SPP1) cytokines, 5 (AR, NR1I2/PXR, NR1I3/CAR, NR2F6, and PPARα) and 7 (AR, ESR1, NR1I2/PXR, NR1I3/CAR, PPARα, RORα/NR1F1, and RORγ) nuclear receptors, and 80 and 113 transcription regulators are found to mediate the relationship between genetic variant and CYP2D6 activity for Affymetrix and Illumina data sets. Overlapped eQTL hotspots with the mediators lead to the identification of 64 transcription factors that can regulate CYP2D6 (Jiang et al. 2013). These transcription factors include AATF, ALYREF, ARHGAP35, ASB8, ATF4, CBX4, CEBPG, CSDA, DDIT3, E2F5, ETV7, FOXN3, FOXN3, FUBP1, GPS2, HDAC10, HMGN1, ID1, INVS, IRF9, KANK1, KAT2B, KHDRBS1, KLF12, MAF, MAML2, MEIS2, MLXIPL, MXD4, MYBBP1A, MYCL1, NCOA7, NCOR1, NFIA, NFKB2, NFYA, NOLC1, NPM1, PEX14, PYCARD, SAP18, SATB1, SIM2, SLC2A4RG, SMARCC1, SNAI3, SNW1, SOX5, TCERG1, TCF7L2, TEAD3, TEAD4, TFDP2, TFEB, TOB1, p53, YWHAB, YY1, ZGPAT, ZHX3, ZKSCAN1, ZNF132, ZNF256, and ZNF263 (Jiang et al. 2013). Among them, YY1 has been reported to putatively bind to human CYP2D6 or rat Cyp2d4 promoter and regulate the expression of CYP2D6 (Gong et al. 2013) and Cyp2d4 (Mizuno et al. 2003). This study has provided new insights into the complex regulatory network for hepatic CYP2D6. Addition of the p53 inhibitor cyclic PFT-α in HepG2 cells dose-dependently enhances CYP2D6 and 3A4 activity, whereas addition of the p53 activator NSC 66811 dose-dependently inhibits CYP2D6 and 3A4 activity (Xiao et al. 2015). Further functional and validation studies are certainly needed to verify the regulation of CYP2D6 by these genes.
Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity
Published in OncoImmunology, 2022
Hanfeng Wang, Yang Fan, Weihao Chen, Zheng Lv, Shengpan Wu, Yundong Xuan, Chenfeng Wang, Yongliang Lu, Tao Guo, Donglai Shen, Fan Zhang, Qingbo Huang, Yu Gao, Hongzhao Li, Xin Ma, Baojun Wang, Yan Huang, Xu Zhang
Although we demonstrated that CMTM6 depletion increases genome instability, leading to following activation of cellular senescence, the underlying mechanisms remains unknown. Dynamic transcriptome profiling of DNA damage-induced cellular senescence predicted that many transcription factors, such as NFYA, PLAU, ATF1, ATF3 and ATF4, may play key roles in regulating DNA repair and senescent cell fates.53 Correspondingly, RNA-seq analysis in our study revealed that levels of NFY-B, NFY-C (another two subunits of the transcription factor NFY), PLAU, ATF1, ATF4, E2F2, E2F3 and RB1 were dramatically changed, as well as RUNX family and ELF4. NFY is known as a classic transcriptional regulator of cell cycle genes in senescence,54 ATF4 is involved in DNA repair.55 In addition, growing evidence implicates RUNX family transcription factors are frequently dysregulated in cancers and function as regulators for DNA damage response.56 ELF4, a member of the ETS family of transcription factors, contributes to the persistence of γH2A.X DNA damage foci and the absence of ELF4 promotes the faster repair of damaged DNA and more rapid disappearance of γH2A.X foci.57 Therefore, we suspected that transcription factors might be involved in CMTM6-mediated DNA damage and following activation of cellular senescence, further research to clarify the underlying mechanisms is urgently needed.
Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response in vitro and in vivo
Published in Stress, 2019
Ting Li-Tempel, Tobias Suer, Tobias Tempel, Mauro F. Larra, Ulrike Winnikes, Hartmut Schächinger, Jobst Meyer, Andrea B. Schote
We focused on two SNPs that were previously shown to impact mainly cAMP-dependent transcription factor binding. Rs3176921 changes the consensus sequence of the binding box of nuclear transcription factor Y (NF-Y) from CCAAT to CCACT, and therewith disrupts NF-Y binding (Wagner et al., 2006) as well as significantly affects the expression of genes involved in complex pathways (Chassanidis et al., 2009; Chen, Mo, Li, Zeng, & Xu, 2007; Dolfini, Gatta, & Mantovani, 2012). Further evidence is accumulating that alteration of the NF-Y structure is not the direct cause of any specific disease. Rather the efficiency of DNA-binding might play a role on the development of several pathological conditions, resulting either in altered proteins, or altered gene expression patterns (Dolfini et al., 2012). Further, rs5030875 is in a high linkage disequilibrium with the SNP rs5030876, which results in the exchange of a nucleotide within the binding site of the transcription factor activating transcription factor 6 (ATF6). ATF6 is a member of the human ARF/CREB (cAMP response element binding protein) family. ATF6 participates in two independent signaling pathways, both leading to transcriptional activation in the nucleus (Yoshida, Haze, Yanagi, Yura, & Mori, 1998), interaction with cAMP responsive elements (Fawcett, Martindale, Guyton, Hai, & Holbrook, 1999), and finally differences in the CRH promoter activity (Wagner et al., 2006).
Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Alejandro Schcolnik-Cabrera, Alma Chávez-Blanco, Guadalupe Domínguez-Gómez, Lucia Taja-Chayeb, Rocio Morales-Barcenas, Catalina Trejo-Becerril, Enrique Perez-Cardenas, Aurora Gonzalez-Fierro, Alfonso Dueñas-González
It is not surprising, after all, that many commonly altered oncogenes and tumor suppressor genes [5–11] activate both PI3K/AKT and ERK/MAPK signaling cascades, which activates the AKT/mTOR pathway that in turn leads to increased expression of positive regulators of FASN mRNA expression including sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate-activated transcription factor response element binding protein (ChREBP) [62,63]. There are additional transcriptional regulators of FASN gene, such as NAC1 [64], P300 acetyltransferase [65], the ubiquitous nuclear transcription factor Y (NF-Y) [65], and signaling via the GPER (G protein-coupled estrogen receptor) [66]. Moreover, in prostate cancer, FASN protein stabilization occurs via USP2a isopeptidase [67].