scholarly journals The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

2015 ◽  
Vol 112 (27) ◽  
pp. 8326-8331 ◽  
Author(s):  
Chiara Pastori ◽  
Philipp Kapranov ◽  
Clara Penas ◽  
Veronica Peschansky ◽  
Claude-Henry Volmar ◽  
...  
Keyword(s):  
Single Molecule ◽  
Noncoding Rna ◽  
Single Molecule Sequencing ◽  
Antiproliferative Effects ◽  
Protein Inhibition ◽  
Control Tumor Growth ◽  
Cancer Initiation ◽  
Bromodomain Proteins ◽  
Control Tumor ◽  
Bet Protein

Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.

scholarly journals EcDNA hubs drive cooperative intermolecular oncogene expression

2020 ◽  
Author(s):  
King L. Hung ◽  
Kathryn E. Yost ◽  
Liangqi Xie ◽  
Sihan Wu ◽  
Joshua T. Lange ◽  
...  
Keyword(s):  
Single Molecule ◽  
Nuclear Bodies ◽  
Distal Enhancer ◽  
Single Molecule Sequencing ◽  
Bet Inhibitor ◽  
Cooperative Evolution ◽  
Oncogene Expression ◽  
Dna Elements ◽  
Altered Gene ◽  
Bet Protein

ABSTRACTExtrachromosomal DNAs (ecDNAs) are prevalent in human cancers and mediate high oncogene expression through elevated copy number and altered gene regulation1. Gene expression typically involves distal enhancer DNA elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs, comprised of ~10-100 ecDNAs clustered in the nucleus of interphase cells, drive intermolecular enhancer input for amplified oncogene expression. Single-molecule sequencing, single-cell multiome, and 3D enhancer connectome reveal subspecies of MYC-PVT1 ecDNAs lacking enhancers that access intermolecular and ectopic enhancer-promoter interactions in ecDNA hubs. ecDNA hubs persist without transcription and are tethered by BET protein BRD4. BET inhibitor JQ1 disperses ecDNA hubs, preferentially inhibits ecDNA oncogene transcription, and kills ecDNA+ cancer cells. Two amplified oncogenes MYC and FGFR2 intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs are nuclear bodies of many ecDNAs tethered by proteins and platforms for cooperative transcription, leveraging the power of oncogene diversification and combinatorial DNA interactions. We suggest ecDNA hubs, rather than individual ecDNAs, as units of oncogene function, cooperative evolution, and new targets for cancer therapy.

scholarly journals EXTH-43. GENERATION OF A B-CELL-BASED VACCINE FOR THE TREATMENT OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii96-ii96
Author(s):  
Catalina Lee Chang ◽  
Jason Miska ◽  
David Hou ◽  
Aida Rashidi ◽  
Peng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cross Presentation ◽  
Control Tumor Growth ◽  
Efficient Alternative ◽  
Control Tumor ◽  
Secondary Lymphoid Organs

Abstract Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

Endoscopic transventricular positioning of intracystic catheter for treatment of craniopharyngioma

2009 ◽  
Vol 4 (3) ◽  
pp. 245-248 ◽  
Author(s):  
Benedetta L. Pettorini ◽  
Gianpiero Tamburrini ◽  
Luca Massimi ◽  
Massimo Caldarelli ◽  
Concezio Di Rocco
Keyword(s):  
Interferon Α ◽  
Ventricular Catheter ◽  
Endoscopic View ◽  
Frontal Horn ◽  
Control Tumor Growth ◽  
Intratumoral Therapy ◽  
Subcutaneous Space ◽  
Control Tumor ◽  
Harmful Effects ◽  
Intracystic Injection

The intracystic injection of chemo- and radiotherapeutic agents was introduced for the treatment of craniopharyngioma to control tumor growth and to delay the potentially harmful effects of surgery or radiation therapy. The positioning of cyst catheters has been performed by means of direct vision, stereotactically guided insertion, and ultrasonographic and ventriculoscopic guidance. The insertion of a catheter into the cyst is not devoid of complications, with an incidence ranging up to 16%, independent of the surgical technique used. Eight patients (mean age 25.8 years) with symptomatic cystic craniopharyngioma were treated by means of an endoscopic transventricular approach for the insertion of an intracystic catheter for intratumoral therapy with interferon-α. A single right precoronal bur hole is made, and the frontal horn of the lateral ventricle is accessed under neuronavigation guidance. A ventricular catheter with an inserted stylet was advanced anterior to the endoscope sheath through the same cortical access as the endoscope and was guided under endoscopic view down to the cyst dome wall. The coagulated surface of the craniopharyngioma cyst was punctured and the tip of the ventricular catheter was advanced; the depth was established preoperatively on MR scans and confirmed by neuronavigation guidance. The proximal end of the cystic catheter was connected to an access chamber to be left in the subcutaneous space, and the endoscope was slowly retracted. The authors' experience favors the use of neuroendoscopic positioning of intracystic catheters as safer than open and stereotactic approaches.

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