China
Africa
Explore chapters and articles related to this topic
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
The human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 6 (CMTM6) has recently been identified as a critical regulator for the expression of programmed death-ligand 1 (PD-L1) and anti-tumor immunity.10,11 Overexpression of CMTM6 is strongly associated with malignant features and poor prognosis in several types of cancers, and targeting CMTM6 suppresses the stem cell-like properties of cancer cells, TGF-β induced epithelial–mesenchymal transition (EMT) and cell proliferation.12–14 Notably, recent studies have revealed that the WEE1 inhibitors, a suppressor of DDR, can downregulate the expression of CMTM6.15 Nevertheless, whether CMTM6 is involved in DNA damage and the specific function and molecular mechanisms of CMTM6 in carcinogenesis, development, and prognosis in ccRCC are still poorly understood.
The tumor microenvironment and triple-negative breast cancer aggressiveness: shedding light on mechanisms and targeting
Published in Expert Opinion on Therapeutic Targets, 2022
Natsuki Furukawa, Vered Stearns, Cesar A. Santa-Maria, Aleksander S. Popel
Several mechanisms have been proposed for the high expression level of PD-L1 in TNBC. In vitro study has shown that silencing of phosphatase and tensin homolog (PTEN) and the subsequent activation of the phosphoinositide 3-kinase (PI3K) signaling increase the expression level of PD-L1 in TNBC cells [30]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is mutated in approximately 9% of TNBC tumors and is the second most frequently mutated gene. PTEN is also a highly mutated gene in TNBC [38]. CKLF-like MARVEL transmembrane domain containing protein 6 (CMTM6) was identified in a genome-wide CRISPR-Cas9 screen seeking genes required for PD-L1 expression. CMTM6 facilitates the recycling of PD-L1 to the cell surface and prevents degradation of PD-L1 in the lysosome [48]. Nucleophosmin (NPM1) is a transcriptional activator that binds to the PD-L1 promoter and increases its expression specifically in TNBC cell lines but not in non-invasive breast cancer cell lines [49].
Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy
Published in OncoImmunology, 2021
Sandra Martinez-Morilla, Jon Zugazagoitia, Pok Fai Wong, Harriet M. Kluger, David L. Rimm
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing family member 6 (CMTM6) was identified in 20037 and is widely expressed at the plasma membrane of several cell types, but only recently it has been identified as a PD-L1 protein stabilizer in two independent large-scale genetic screenings, which regulates T cell function.8,9 CMTM6 inhibits ubiquitination of PD-L1 and subsequent degradation via lysosomes, promoting stabilization of PD-L1 in the membrane. In addition, downregulation of CMTM6 gives rise to PD-L1 reduction, constitutively and interferon gamma (IFN-ɣ)-dependent, in cancer cells, dendritic cells, and xenografts derived from patients with melanoma, with no effect on PD-L1 mRNA levels.9 Furthermore, CMTM6, alone or in combination with PD-L1, has shown prognostic10–12 and predictive13,14 value in a variety of cancers. Despite all these findings, there have been few efforts to determine the predictive value of CMTM6, alone or colocalizing with PD-L1 for melanoma immunotherapy.