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https://read.qxmd.com/read/30753828/aging-like-spontaneous-epigenetic-silencing-facilitates-wnt-activation-stemness-and-braf-v600e-induced-tumorigenesis
#1
Yong Tao, Byunghak Kang, Daniel A Petkovich, Yuba R Bhandari, Julie In, Genevieve Stein-O'Brien, Xiangqian Kong, Wenbing Xie, Nicholas Zachos, Shinji Maegawa, Himani Vaidya, Stephen Brown, Ray-Whay Chiu Yen, Xiaojian Shao, Jai Thakor, Zhihao Lu, Yi Cai, Yuezheng Zhang, Izaskun Mallona, Miguel Angel Peinado, Cynthia A Zahnow, Nita Ahuja, Elana Fertig, Jean-Pierre Issa, Stephen B Baylin, Hariharan Easwaran
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E , producing the typical human proximal BRAFV600E -driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP)...
February 11, 2019: Cancer Cell
https://read.qxmd.com/read/30485824/integrated-genomic-epigenomic-and-expression-analyses-of-ovarian-cancer-cell-lines
#2
Eniko Papp, Dorothy Hallberg, Gottfried E Konecny, Daniel C Bruhm, Vilmos Adleff, Michaël Noë, Ioannis Kagiampakis, Doreen Palsgrove, Dylan Conklin, Yasuto Kinose, James R White, Michael F Press, Ronny Drapkin, Hariharan Easwaran, Stephen B Baylin, Dennis Slamon, Victor E Velculescu, Robert B Scharpf
To improve our understanding of ovarian cancer, we performed genome-wide analyses of 45 ovarian cancer cell lines. Given the challenges of genomic analyses of tumors without matched normal samples, we developed approaches for detection of somatic sequence and structural changes and integrated these with epigenetic and expression alterations. Alterations not previously implicated in ovarian cancer included amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and TGF-beta receptor pathway members, and rearrangements of YAP1-MAML2 and IKZF2-ERBB4...
November 27, 2018: Cell Reports
https://read.qxmd.com/read/30454645/targeting-cdk9-reactivates-epigenetically-silenced-genes-in-cancer
#3
Hanghang Zhang, Somnath Pandey, Meghan Travers, Hongxing Sun, George Morton, Jozef Madzo, Woonbok Chung, Jittasak Khowsathit, Oscar Perez-Leal, Carlos A Barrero, Carmen Merali, Yasuyuki Okamoto, Takahiro Sato, Joshua Pan, Judit Garriga, Natarajan V Bhanu, Johayra Simithy, Bela Patel, Jian Huang, Noël J-M Raynal, Benjamin A Garcia, Marlene A Jacobson, Cigall Kadoch, Salim Merali, Yi Zhang, Wayne Childers, Magid Abou-Gharbia, John Karanicolas, Stephen B Baylin, Cynthia A Zahnow, Jaroslav Jelinek, Xavier Graña, Jean-Pierre J Issa
Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation...
November 15, 2018: Cell
https://read.qxmd.com/read/30185548/dual-inhibition-of-dna-and-histone-methyltransferases-increases-viral-mimicry-in-ovarian-cancer-cells
#4
Minmin Liu, Stacey L Thomas, Ashley K DeWitt, Wanding Zhou, Zachary B Madaj, Hitoshi Ohtani, Stephen B Baylin, Gangning Liang, Peter A Jones
Ovarian cancer ranks as the most deadly gynecologic cancer, and there is an urgent need to develop more effective therapies. Previous studies have shown that G9A, a histone methyltransferase that catalyzes mono- and dimethylation of histone H3 lysine9, is highly expressed in ovarian cancer tumors, and its overexpression is associated with poor prognosis. Here we report that pharmacologic inhibition of G9A in ovarian cancer cell lines with high levels of G9A expression induces synergistic antitumor effects when combined with the DNA methylation inhibitor (DNMTi) 5-aza-2'-deoxycytidine (5-aza-CdR)...
October 15, 2018: Cancer Research
https://read.qxmd.com/read/30181297/reply-to-haffner-et-al-dna-hypomethylation-renders-tumors-more-immunogenic
#5
LETTER
Meredith L Stone, Katherine B Chiappinelli, Huili Li, Lauren M Murphy, Meghan E Travers, Michael J Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang, Chien-Fu Hung, Vipul Bhargava, Karla R Wiehagen, Glenn S Cowley, Kurtis E Bachman, Reiner Strick, Pamela L Strissel, Stephen B Baylin, Cynthia A Zahnow
No abstract text is available yet for this article.
September 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30097434/a-phase-i-trial-of-a-guadecitabine-sgi-110-and-irinotecan-in-metastatic-colorectal-cancer-patients-previously-exposed-to-irinotecan
#6
Valerie Lee, Judy S Wang, Marianna L Zahurak, Elske C Gootjes, Henk M W Verheul, Rose M Parkinson, Zachary Kerner, Anup Sharma, Gary L Rosner, Ana De Jesus-Acosta, Daniel A Laheru, Dung T Le, Aram Oganesian, Ellen Lilly-Foreman, Thomas Brown, Peter A Jones, Stephen B Baylin, Nita Ahuja, Nilofer A Azad
PURPOSE: Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in mCRC patients previously treated with irinotecan. EXPERIMENTAL DESIGN: In this 3+3 dose-escalation study, mCRC patients previously exposed to irinotecan received guadecitabine days 1-5 of a 28 day cycle and irinotecan 125mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45mg/m2; DL -1: guadecitabine 30mg/m2; DL -1G: guadecitabine 30mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45mg/m2 with GFS...
August 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://read.qxmd.com/read/29615458/an-effective-epigenetic-parp-inhibitor-combination-therapy-for-breast-and-ovarian-cancers-independent-of-brca-mutations
#7
Nicholas Pulliam, Fang Fang, Ali R Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold Keer, John Lyons, Stephen B Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V Rassool, Kathy D Miller, Kenneth P Nephew
Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status...
July 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://read.qxmd.com/read/29438699/dna-methylation-patterns-separate-senescence-from-transformation-potential-and-indicate-cancer-risk
#8
Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L F Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A Zahnow, Nita Ahuja, Stephen B Baylin, Hariharan Easwaran
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation...
February 12, 2018: Cancer Cell
https://read.qxmd.com/read/29381856/biochemical-studies-and-molecular-dynamic-simulations-reveal-the-molecular-basis-of-conformational-changes-in-dna-methyltransferase-1
#9
Fei Ye, Xiangqian Kong, Hao Zhang, Yan Liu, Zhiyuan Shao, Jia Jin, Yi Cai, Rukang Zhang, Linjuan Li, Yang W Zhang, Yu-Chih Liu, Chenhua Zhang, Wenbing Xie, Kunqian Yu, Hong Ding, Kehao Zhao, Shijie Chen, Hualiang Jiang, Stephen B Baylin, Cheng Luo
DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity. The mutations of N1248A and R1279D, which did not affect interactions between DNMT1 and substrates or cofactors, allosterically reduced enzymatic activities in vitro by decreasing kcat / Km for AdoMet...
March 16, 2018: ACS Chemical Biology
https://read.qxmd.com/read/29367758/the-tumor-suppressor-hic1-maintains-chromosomal-stability-independent-of-tp53
#10
Anette Szczepny, Kirstyn Carey, Lisa McKenzie, W Samantha N Jayasekara, Fernando Rossello, Alvaro Gonzalez-Rajal, Andrew S McCaw, Dean Popovski, Die Wang, Anthony J Sadler, Annabelle Mahar, Prudence A Russell, Gavin Wright, Rachael A McCloy, Daniel J Garama, Daniel J Gough, Stephen B Baylin, Andrew Burgess, Jason E Cain, D Neil Watkins
Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex...
January 25, 2018: Oncogene
https://read.qxmd.com/read/29282222/a-kdm5-inhibitor-increases-global-h3k4-trimethylation-occupancy-and-enhances-the-biological-efficacy-of-5-aza-2-deoxycytidine
#11
Benjamin R Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B Baylin
The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA-demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes...
March 1, 2018: Cancer Research
https://read.qxmd.com/read/29203668/epigenetic-therapy-activates-type-i-interferon-signaling-in-murine-ovarian-cancer-to-reduce-immunosuppression-and-tumor-burden
#12
Meredith L Stone, Katherine B Chiappinelli, Huili Li, Lauren M Murphy, Meghan E Travers, Michael J Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang, Chien-Fu Hung, Vipul Bhargava, Karla R Wiehagen, Glenn S Cowley, Kurtis E Bachman, Reiner Strick, Pamela L Strissel, Stephen B Baylin, Cynthia A Zahnow
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy...
December 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/29195073/epigenetic-therapy-ties-myc-depletion-to-reversing-immune-evasion-and-treating-lung-cancer
#13
Michael J Topper, Michelle Vaz, Katherine B Chiappinelli, Christina E DeStefano Shields, Noushin Niknafs, Ray-Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew Ballew, Meredith Stone, Phuoc T Tran, Cynthia A Zahnow, Matthew D Hellmann, Valsamo Anagnostou, Pamela L Strissel, Reiner Strick, Victor E Velculescu, Stephen B Baylin
Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction...
November 30, 2017: Cell
https://read.qxmd.com/read/28898697/chronic-cigarette-smoke-induced-epigenomic-changes-precede-sensitization-of-bronchial-epithelial-cells-to-single-step-transformation-by-kras-mutations
#14
Michelle Vaz, Stephen Y Hwang, Ioannis Kagiampakis, Jillian Phallen, Ashwini Patil, Heather M O'Hagan, Lauren Murphy, Cynthia A Zahnow, Edward Gabrielson, Victor E Velculescu, Hariharan P Easwaran, Stephen B Baylin
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer...
September 11, 2017: Cancer Cell
https://read.qxmd.com/read/28622390/inhibiting-dna-methylation-activates-cancer-testis-antigens-and-expression-of-the-antigen-processing-and-presentation-machinery-in-colon-and-ovarian-cancer-cells
#15
Cornelia Siebenkäs, Katherine B Chiappinelli, Angela A Guzzetta, Anup Sharma, Jana Jeschke, Rajita Vatapalli, Stephen B Baylin, Nita Ahuja
Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues...
2017: PloS One
https://read.qxmd.com/read/28486105/chd4-has-oncogenic-functions-in-initiating-and-maintaining-epigenetic-suppression-of-multiple-tumor-suppressor-genes
#16
Limin Xia, Wenjie Huang, Marina Bellani, Michael M Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W Zhang, Li-Rong Yu, Huili Li, Cynthia A Zahnow, Wenbing Xie, Ray-Whay Chiu Yen, Feyruz V Rassool, Stephen B Baylin
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks...
May 8, 2017: Cancer Cell
https://read.qxmd.com/read/28445481/hypomethylating-agents-synergize-with-irinotecan-to-improve-response-to-chemotherapy-in-colorectal-cancer-cells
#17
Anup Sharma, Rajita Vatapalli, Eihab Abdelfatah, K Wyatt McMahon, Zachary Kerner, Angela A Guzzetta, Jasvinder Singh, Cynthia Zahnow, Stephen B Baylin, Sashidhar Yerram, Yue Hu, Nilofer Azad, Nita Ahuja
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment...
2017: PloS One
https://read.qxmd.com/read/28407701/correction-a-new-immunohistochemistry-prognostic-score-ips-for-recurrence-and-survival-in-resected-pancreatic-neuroendocrine-tumors-pannet
#18
Antonio Viúdez, Filipe L F Carvalho, Zahra Maleki, Marianna Zahurak, Daniel Laheru, Alejandro Stark, Nilofer S Azad, Christopher L Wolfgang, Stephen Baylin, James G Herman, Ana De Jesus-Acosta
No abstract text is available yet for this article.
March 14, 2017: Oncotarget
https://read.qxmd.com/read/28388418/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#19
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
April 6, 2017: Cell
https://read.qxmd.com/read/28202634/dietary-patterns-are-associated-with-metabolic-outcomes-among-adult-samoans-in-a-cross-sectional-study
#20
Dongqing Wang, Nicola L Hawley, Avery A Thompson, Viali Lameko, Muagatutia Sefuiva Reupena, Stephen T McGarvey, Ana Baylin
Background: The Samoan population has been undergoing a nutrition transition toward more imported and processed foods and a more sedentary lifestyle. Objectives: We aimed to identify dietary patterns in Samoa and to evaluate their associations with metabolic outcomes. Methods: The sample of this cross-sectional study includes 2774 Samoan adults recruited in 2010 (1104 with metabolic syndrome compared with 1670 without). Principal component analysis on food items from a 104-item food-frequency questionnaire was used to identify dietary patterns...
April 2017: Journal of Nutrition
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