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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.
Targeting leukemia inhibitory factor in pancreatic adenocarcinoma
Published in Expert Opinion on Investigational Drugs, 2023
Jing Wang, Christian Karime, Umair Majeed, Jason S. Starr, Mitesh J. Borad, Hani M. Babiker
Although more studies are required to elucidate the mechanisms whether LIF acts on the cancer cells in an autocrine or paracrine manner, it has been demonstrated that activation of the Hippo pathway affects cancer growth in a ‘feed-forward’ autocrine manner [49]. (Figure 3) LIF activates YES, which subsequently increases tyrosine phosphorylation of YAP. In ovarian cancer cell lines, YAP induces the upregulation of epidermal growth factor (EGF) receptors (EGFR) and thus the production of EGF-like agonists, NRG1, and HBEGF. NRG1 and HBEGF in turn activates YAP in a feed-forward autocrine fashion and stimulates cancer cell growth [50]. In colorectal cancer (CRC), gp130 was identified as a YAP-TEAD4 target gene that augment activation of YAP via tyrosine phosphorylation by Src family kinases (SFK) [51]. Notably, the YAP mRNA levels and transcriptional activity are upregulated by prostaglandin E2 (PGE2). Thus, the upregulation of the PGE2-producing enzyme was associated with increased YAP transcription, and this process is mediated through a YAP-TEAD4 mechanism. The end result was a feed-forward PGE2 signaling mechanism through YAP autocrine signaling [52]. (Figure 3)
Long-Term Glucose Restriction with or without β-Hydroxybutyrate Enrichment Distinctively Alters Epithelial-Mesenchymal Transition-Related Signalings in Ovarian Cancer Cells
Published in Nutrition and Cancer, 2021
Hossein Ghahremani, Saeedeh Nabati, Hanieh Tahmori, Tahmineh Peirouvi, Majid Sirati-Sabet, Siamak Salami
Dysfunctional Hippo pathway is one of the contributing factors in pathological conditions such as developmental defects, overgrowth, and cancer (57). It has been reported that the amount of oncogenic YAP protein is amplified in ovarian epithelial cancers (58). Moreover, the concomitant expression of YAP and TEAD4 transcription factors have been considered as an indicator of poor prognosis for the survival of patients with ovarian cancer (59,60). In our study, glucose restriction was not able to reduce its expression, but the expression of YAP was decreased after bHB enrichment. In recent years, a strong association has been observed between glucose metabolism and YAP activity (61). Likewise, in the present study, we observed that the expression of the YAP, in the gene and protein levels, did not change by glucose depletion alone in both A2780CP and SK-OV-3 cells, but bHB enrichment significantly reduced YAP in glucose restricted cells. To the best of our knowledge, the effect of bHB enrichment has not been reported yet.
Hippo pathway inhibition by blocking the YAP/TAZ–TEAD interface: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
James J. Crawford, Sarah M. Bronner, Jason R. Zbieg
When one considers targeting the Hippo pathway as a therapeutic approach, it is immediately obvious that inhibiting a number of the pathway members including the core kinase cascade might be problematic, as Nf2, Mst1/2, and Lats1/2 are known tumor suppressors. Furthermore, the optimal approach to activate these targets is not readily apparent. The most plausible strategy to target the Hippo pathway is through the transcriptional coactivators YAP and TAZ, along with the TEADs. These proteins have been the subject of a number of studies, and it is known that YAP and TAZ are intrinsically disorganized proteins [17] and would therefore be challenging to modulate with small molecule binders. One potential strategy might be sequestrating YAP in the cytoplasm, thereby blocking its transcriptional activity in combination with TEADs. In a combined effort, the research groups of Wang and Zhu have shown that verteporfin inhibits YAP’s ability to function by upregulating 14–3-3α, a YAP chaperon protein that does not allow YAP to migrate to the nucleus and targets it for degradation via the proteasome [18]. In the case of TEADs, significant effort has been expended with the goal of elucidating their structures and crucial residues for binding, interaction, and signaling. While in Drosophilia there is only one TEAD-equivalent gene, there known as Scalloped, four TEAD genes exist in mammals (TEAD1, TEAD2, TEAD3, and TEAD4). The TEADs are multi-domain nuclear transcription factors comprised of an N-terminal TEA domain, a DNA binding domain (a.k.a. the DBD), a proline-rich region, and a C-terminal YAP/TAZ binding domain [19].