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  • 1
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    Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 12 ( 2016-03-22), p. 3317-3322
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 12 ( 2016-03-22), p. 3317-3322
    Abstract: Multiple factors, including host genetics, environmental factors, and Epstein–Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor ( MST1R ) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germ-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10 −12 ). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1523436113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 2
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    EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 28 ( 2019-07-09), p. 14144-14153
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 28 ( 2019-07-09), p. 14144-14153
    Abstract: Epstein−Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1 , involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1821752116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 3
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    Targeting mitochondria for cancer photodynamic therapy
    Elsevier BV ; 2022
    In:  Photodiagnosis and Photodynamic Therapy Vol. 38 ( 2022-06), p. 102830-
    Details
    In: Photodiagnosis and Photodynamic Therapy, Elsevier BV, Vol. 38 ( 2022-06), p. 102830-
    Type of Medium: Online Resource
    ISSN: 1572-1000
    URL: Article
    DOI: 10.1016/j.pdpdt.2022.102830
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 4
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    PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma
    Impact Journals, LLC ; 2015
    In:  Oncotarget Vol. 6, No. 15 ( 2015-05-30), p. 13434-13447
    Details
    In: Oncotarget, Impact Journals, LLC, Vol. 6, No. 15 ( 2015-05-30), p. 13434-13447
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    URL: Article
    DOI: 10.18632/oncotarget.v6i15
    DOI: 10.18632/oncotarget.3876
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2015
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  • 5
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    Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci
    Springer Science and Business Media LLC ; 2020
    In:  Communications Biology Vol. 3, No. 1 ( 2020-12-11)
    Details
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 3, No. 1 ( 2020-12-11)
    Abstract: Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 ( T rs2517664  = 4.6%, P  = 6.38 × 10 −21 ) and rs117495548 ( G rs117495548  = 3.0%, P  = 4.53 × 10 −13 ), map near TRIM31 and TRIM39 / TRIM39-RPP21 ; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 ( P  = 1.77 × 10 −36 ). The rare HLA-B*07:05 allele (OR  〈  0.015, P  = 5.83 × 10 −21 ) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39 , impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    URL: Article
    DOI: 10.1038/s42003-020-01487-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 6
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    Leukocyte telomere length associates with nasopharyngeal carcinoma risk and survival in H ong K ong C hinese
    Wiley ; 2018
    In:  International Journal of Cancer Vol. 143, No. 9 ( 2018-11), p. 2289-2298
    Details
    In: International Journal of Cancer, Wiley, Vol. 143, No. 9 ( 2018-11), p. 2289-2298
    Abstract: What's new? Telomere length can contribute to age‐related diseases, including cancer. These authors measured telomere length in leukocytes to look for a relationship with nasopharyngeal carcinoma (NPC). Shorter telomeres, they found, associated with increased risk of NPC. Somewhat surprisingly, people with suboptimal telomere length, either shorter or longer than average, appeared to have increased risk of late‐stage disease and poorer survival. Measuring blood telomere length could provide a simple, non‐invasive prognostic test for NPC.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v143.9
    DOI: 10.1002/ijc.31617
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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  • 7
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    A DNA tumor virus globally reprograms host 3D genome architecture to achieve immortal growth
    Springer Science and Business Media LLC ; 2023
    In:  Nature Communications Vol. 14, No. 1 ( 2023-03-22)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-03-22)
    Abstract: Epstein-Barr virus (EBV) immortalization of resting B lymphocytes (RBLs) to lymphoblastoid cell lines (LCLs) models human DNA tumor virus oncogenesis. RBL and LCL chromatin interaction maps are compared to identify the spatial and temporal genome architectural changes during EBV B cell transformation. EBV induces global genome reorganization where contact domains frequently merge or subdivide during transformation. Repressed B compartments in RBLs frequently switch to active A compartments in LCLs. LCLs gain 40% new contact domain boundaries. Newly gained LCL boundaries have strong CTCF binding at their borders while in RBLs, the same sites have much less CTCF binding. Some LCL CTCF sites also have EBV nuclear antigen (EBNA) leader protein EBNALP binding. LCLs have more local interactions than RBLs at LCL dependency factors and super-enhancer targets. RNA Pol II HiChIP and FISH of RBL and LCL further validate the Hi-C results. EBNA3A inactivation globally alters LCL genome interactions. EBNA3A inactivation reduces CTCF and RAD21 DNA binding. EBNA3C inactivation rewires the looping at the CDKN2A/B and AICDA loci. Disruption of a CTCF site at AICDA locus increases AICDA expression. These data suggest that EBV controls lymphocyte growth by globally reorganizing host genome architecture to facilitate the expression of key oncogenes.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-023-37347-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 8
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    Abstract 5192: EBV-associated histone modifications regulate DNA damage repair pathway and associate with cisplatin resistance in nasopharyngeal epithelial malignancy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5192-5192
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5192-5192
    Abstract: Introduction: Epstein-Barr virus (EBV) infection is associated with various cancers. Some studies have confirmed EBV can induce hypermethylation to suppress the expression of several key cancer-related genes in gastric cancer. Previously, we showed that nasopharyngeal carcinoma (NPC), an EBV-associated malignancy, is characterized by low mutation rate, but harbors extensive hypermethylation compared with other cancer types. Also, the de novo methylated regions in NPC extensively overlap with the histone bivalent marks (H3K4me3 and H3K27me3) derived from human embryonic stem cells . This suggests an important role of EBV in regulating histone modifications in NPC development. Hence, further studies focusing on the EBV-associated histone modifications are necessary. Aim: This study aims to elucidate the role of EBV in regulating a transcription-activation histone mark (H3K4me3) and a suppressive mark (H3K27me3) in nasopharyngeal epithelial (NPE) cells. Methodologies: Two pairs of EBV+/- NPE cell lines were used for chromatin immunoprecipitation sequencing (ChIP-Seq) to identify the genes regulated by EBV-associated histone modifications. ChIP-QPCR and RT-QPCR were utilized to validate the ChIP-Seq results. The candidate genes and pathways identified from the ChIP-Seq results were validated by in vitro and in vivo functional studies. Results: A panel of 16 DNA damage repair family members were identified with significant reduction of H3K4me3 in the EBV+ NPE cells. One of the candidate genes, MLH1, was validated with down-regulation in the EBV+ NPC cell lines and NPC specimens, and the expression level was demonstrated to associate with cisplatin resistance. Also, the base excision repair (BER) pathway was significantly enriched with reduction of H3K4me3 after EBV infection. Down-regulation of the 7 members from BER was validated in the EBV+ NPE cell lines and NPC specimens. The defective DNA damage repair in the EBV+ NPE cell lines was further validated by the comet assay. Furthermore, after EBV infection, gain of H3K27me3 in MLH1 and the 7 members from BER pathway was identified by ChIP-QPCR. Interestingly, our results from bisulfite sequencing reveals that the promoter regions of the candidate genes are hypomethylated in both EBV +/- NPE cells. Conclusion: EBV modulates histone bivalent marks independent of the promoter DNA methylation status to regulate DNA damage repair in the host cells. Acknowledgements: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People’s Republic of China: Grant number AoE/M-06/08 to MLL and Seed Funding Programme for Basic Research of HKU 201308159003 to AKLC. Citation Format: Merrin Man Long Leong, Arthur Kwok Leung Cheung, Wei Dai, Sai Wah Tsao, Maria Li Lung. EBV-associated histone modifications regulate DNA damage repair pathway and associate with cisplatin resistance in nasopharyngeal epithelial malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5192.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-5192
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    The Epstein-Barr Virus Enhancer Interaction Landscapes in Virus-Associated Cancer Cell Lines
    American Society for Microbiology ; 2022
    In:  Journal of Virology Vol. 96, No. 18 ( 2022-09-28)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 96, No. 18 ( 2022-09-28)
    Abstract: Epstein-Barr virus (EBV) persists in human cells as episomes. EBV episomes are chromatinized and their 3D conformation varies greatly in cells expressing different latency genes. We used HiChIP, an assay which combines genome-wide chromatin conformation capture followed by deep sequencing (Hi-C) and chromatin immunoprecipitation (ChIP), to interrogate the EBV episome 3D conformation in different cancer cell lines. In an EBV-transformed lymphoblastoid cell line (LCL) GM12878 expressing type III EBV latency genes, abundant genomic interactions were identified by H3K27ac HiChIP. A strong enhancer was located near the BILF2 gene and looped to multiple genes around BALFs loci. Perturbation of the BILF2 enhancer by CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) altered the expression of BILF2 enhancer-linked genes, including BARF0 and BALF2, suggesting that this enhancer regulates the expression of linked genes. H3K27ac ChIP followed by deep sequencing (ChIP-seq) identified several strong EBV enhancers in T/NK (natural killer) lymphoma cells that express type II EBV latency genes. Extensive intragenomic interactions were also found which linked enhancers to target genes. A strong enhancer at BILF2 also looped to the BALF loci. CRISPRi also validated the functional connection between BILF2 enhancer and BARF1 gene. In contrast, H3K27ac HiChIP found significantly fewer intragenomic interactions in type I EBV latency gene-expressing primary effusion lymphoma (PEL) cell lines. These data provided new insight into the regulation of EBV latency gene expression in different EBV-associated tumors. IMPORTANCE EBV is the first human DNA tumor virus identified, discovered over 50 years ago. EBV causes ~200,000 cases of various cancers each year. EBV-encoded oncogenes, noncoding RNAs, and microRNAs (miRNAs) can promote cell growth and survival and suppress senescence. Regulation of EBV gene expression is very complex. The viral C promoter regulates the expression of all EBV nuclear antigens (EBNAs), some of which are very far away from the C promoter. Another way by which the virus activates remote gene expression is through DNA looping. In this study, we describe the viral genome looping patterns in various EBV-associated cancer cell lines and identify important EBV enhancers in these cells. This study also identified novel opportunities to perturb and eventually control EBV gene expression in these cancer cells.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00739-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
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  • 10
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    The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies
    Frontiers Media SA ; 2021
    In:  Frontiers in Oncology Vol. 11 ( 2021-2-25)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-2-25)
    Abstract: Epstein-Barr virus (EBV) infection is associated with a variety of malignancies including Burkitt’s lymphoma (BL), Hodgkin’s disease, T cell lymphoma, nasopharyngeal carcinoma (NPC), and ∼10% of cases of gastric cancer (EBVaGC). Disruption of epigenetic regulation in the expression of tumor suppressor genes or oncogenes has been considered as one of the important mechanisms for carcinogenesis. Global hypermethylation is a distinct feature in NPC and EBVaGC, whereas global reduction of H3K27me3 is more prevalent in EBVaGC and EBV-transformed lymphoblastoid cells. In BL, EBV may even usurp the host factors to epigenetically regulate its own viral gene expression to restrict latency and lytic switch, resulting in evasion of immunosurveillance. Furthermore, in BL and EBVaGC, the interaction between the EBV episome and the host genome is evident with respectively unique epigenetic features. While the interaction is associated with suppression of gene expression in BL, the corresponding activity in EBVaGC is linked to activation of gene expression. As EBV establishes a unique latency program in these cancer types, it is possible that EBV utilizes different latency proteins to hijack the epigenetic modulators in the host cells for pathogenesis. Since epigenetic regulation of gene expression is reversible, understanding the precise mechanisms about how EBV dysregulates the epigenetic mechanisms enables us to identify the potential targets for epigenetic therapies. This review summarizes the currently available epigenetic profiles of several well-studied EBV-associated cancers and the relevant distinct mechanisms leading to aberrant epigenetic signatures due to EBV.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    DOI: 10.3389/fonc.2021.629780
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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