Zhen Lin

Tulane University

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Erik K. Flemington

Tulane University

Michael J. Strong

University of Michigan–Ann Arbor

Melody Baddoo

Tulane University

Christopher M. Taylor

Louisiana State University Health Sciences Center New Orleans

Zhiqiang Qin

Winthrop Rockefeller Foundation

Lu Dai

Winthrop Rockefeller Foundation

Claire Fewell

Tulane University

Qinyan Yin

Tulane University

Eugene Blanchard

Louisiana State University Health Sciences Center New Orleans

Marcus Ware

Ochsner Medical Center

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Tulane University

120

Louisiana Cancer Research Center

Chinese Academy of Sciences

Sun Yat-sen University

Louisiana State University Health Sciences Center New Orleans

Central South University

Louisiana State University

Tulane Medical Center

University of Wisconsin–Madison

University of New Orleans

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Differences in Gastric Carcinoma Microenvironment Stratify According to EBV Infection Intensity: Implications for Possible Immune Adjuvant Therapy

PLoS Pathogens (2013)

Michael J. Strong Guorong Xu Joseph Coco Carl Baribault Dass S. Vinay

Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.

BZLF1

Tumor-infiltrating lymphocytes

ARID1A

10.1371/journal.ppat.1003341

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Citations (148)

Transcriptional coupling of telomeric retrotransposons with the cell cycle

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Mengmeng Liu Xiaojun Xie Xiao Li Xingjie Ren Jasmine Sun

Abstract Instead of employing telomerases to safeguard chromosome ends, dipteran species maintain their telomeres by transposition of telomeric-specific retrotransposons (TRs): in Drosophila , these are HeT-A , TART , and TAHRE . Previous studies have shown how these TRs create tandem repeats at chromosome ends, but the exact mechanism controlling TR transcription has remained unclear. Here we report the identification of multiple subunits of the transcription cofactor Mediator complex and transcriptional factors Scalloped (Sd, the TEAD homolog in flies) and E2F1-Dp as novel regulators of TR transcription and telomere length in Drosophila . Depletion of multiple Mediator subunits, Dp, or Sd increased TR expression and telomere length, while over-expressing E2F1-Dp or knocking down the E2F1 regulator Rbf1 (Retinoblastoma-family protein 1) stimulated TR transcription, with Mediator and Sd affecting TR expression through E2F1-Dp. The CUT&RUN analysis revealed direct binding of CDK8, Dp, and Sd to telomeric repeats. These findings highlight the essential role of the Mediator complex in maintaining telomere homeostasis by regulating TR transcription through E2F1-Dp and Sd, revealing the intricate coupling of TR transcription with the host cell-cycle machinery, thereby ensuring chromosome end protection and genomic stability during cell division.

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10.1101/2023.09.30.560321

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Citations (1)

Induction of a novel isoform of the lnc RNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

Molecular Oncology (2017)

Miao Li Xi Li Yan Zhuang Erik K. Flemington Zhen Lin

Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin-low MDA-MB-231 and Hs578T cells in two-dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin-rich extracellular matrix-based three-dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR-specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR-N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR-N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR-N promoter in Claudin-low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin-low breast cancer cells in lrECM 3D culture.

HOTAIR

Claudin

10.1002/1878-0261.12133

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Citations (30)

Comparative profiling of miRNA expression of lung adenocarcinoma cells in two-dimensional and three-dimensional cultures

Gene (2012)

Cui Li Hong T. Nguyen Yan Zhuang Zhen Lin Erik K. Flemington

10.1016/j.gene.2012.09.093

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Citations (19)

Additional file 10: File S7 of A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus - tumor association

Figshare (2016)

Michael J. Strong Eugene Blanchard Zhen Lin Cindy Morris Melody Baddoo

WGS meningioma. (XLS 61Â kb)

Human virome

10.6084/m9.figshare.c.3645341_d7

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Correction for Strong et al., Epstein-Barr Virus and Human Herpesvirus 6 Detection in a Non-Hodgkin's Diffuse Large B-Cell Lymphoma Cohort by Using RNA Sequencing

Journal of Virology (2015)

Michael J. Strong Tina O’Grady Zhen Lin Guorong Xu Melody Baddoo

10.1128/jvi.02772-15

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CDK11 Promotes Centromeric Transcription to Maintain Centromeric Cohesion during Mitosis

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Qian Zhang Yujue Chen Zhen Teng Zhen Lin Hong Liu

Abstract Actively-transcribing RNA polymerase (RNAP)II is remained on centromeres to maintain centromeric cohesion during mitosis although it is largely released from chromosome arms. This pool of RNAPII plays an important role in centromere functions. However, the mechanism of RNAPII retention on mitotic centromeres is poorly understood. We here demonstrate that Cdk11 depletion-induced centromeric cohesion defects are largely independent of Bub1. We further show that Cdk11 depletion and expression of its kinase-dead version significantly reduce both RNAPII and elongating RNAPII (pSer2) levels on centromeres, and also decrease centromeric transcription without altering the protein expression of cohesin and cohesion-regulators. Interestingly, enhanced centromeric transcription by THZ1 treatment or overexpression of CENP-B DNA-binding domain completely rescues Cdk11-depletion defects. These results suggest that Cdk11 promotes centromeric cohesion through facilitating centromeric transcription. Mechanistically, Cdk11 binds and phosphorylates RNAPII to promote transcription. Furthermore, mitosis-specific degradation of G2/M Cdk11-p58 recapitulates Cdk11-depletion defects. Altogether, our findings establish Cdk11 as an important regulator of centromeric transcription and as part of the mechanism for retaining RNAPII on centromeres during mitosis.

Transcription

PLK1

10.1101/2022.02.01.478617

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Targeting Sphingosine Kinase by ABC294640 against Diffuse Intrinsic Pontine Glioma (DIPG)

Journal of Cancer (2020)

Lu Dai Jungang Chen Zhen Lin Zhaoxiong Wang Shengyu Mu

As a highly aggressive pediatric brainstem tumor, diffuse intrinsic pontine glioma (DIPG) accounts for 10% to 20% of childhood brain tumors.The survival rate for DIPG remains very low, with a median survival time as less than one year even under radiotherapy, the current standard treatment.Moreover, over than 250 clinical trials have failed when trying to improve the survival compared to radiotherapy.The sphingolipid metabolism and related signaling pathways have been found closely related to cancer cell survival; however, the sphingolipid metabolism targeted therapies have never been investigated in DIPG.In the current study, the anti-DIPG activity of ABC294640, the only first-in-class orally available Sphingosine kinase (SphK) inhibitor was explored.Treatment with ABC294640 significantly repressed DIPG cell growth by inducing intracellular pro-apoptotic ceramides production and cell apoptosis.We also profiled ABC294640-induced changes in gene expression within DIPG cells and identified many new genes tightly controlled by sphingolipid metabolism, such as IFITM1 and KAL1.These genes are required for DIPG cell survival and display clinical relevance in DIPG patients' samples.Together, our findings in this study indicate that targeting sphingolipid metabolism may represent a promising strategy to improve DIPG treatment.

Sphingolipid

Sphingosine Kinase

10.7150/jca.46269

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The Pathogenesis and Therapeutics of Nasopharyngeal Carcinoma

ICUS and Nursing Web Journal (2019)

Ji-Qun He Lichun Sun Jun He Chenhong Zhu Ping Li

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma and arises from nasopharynx epithelium, with a geographical and racial distribution. NPC is rare all over the world, but particularly prevalent in Southern China. NPC has been demonstrated to be strongly associated with environmental factors, genetic susceptibility and viral infection, especially Epstein–Barr virus (EBV) infection. NPC is also radio-sensitive and chemo-sensitive. Thus, radiotherapy and chemotherapy are traditional strategies for NPC treatments. However, recurrence frequently occurred in patients after NPC therapeutics. As with the development of new scientific technologies, we get chances to open our mind and dig deep down inside NPC and EBV. A well-understanding of such NPC genetics, gene aberration, non-coding RNA and EBV-associated exosomes, is and will be very helpful for us to promote NPC treatments or develop novel anti-NPC/anti-EBV drugs.

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Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas

PLoS Pathogens (2023)

Jungang Chen Zhenyu Wang Phuc Tran Zhigang Xu Donglin Yang

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.

Primary effusion lymphoma

BRD4

10.1371/journal.ppat.1011089

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Citations (4)