The Innate Immune System and the TRAIL-Bcl-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.

There is a significant sex bias in lung cancer, with males showing increased mortality compared with females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex bias in humanized mice, with male patient-derived xenograft lung tumors being more progressive and deadlier than female patient-derived xenograft lung tumors, we identified mouse tumor models of lung cancer with the same sex bias.

Large-scale integration of DNA methylation and gene expression array platforms identifies both and relationships.

Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene.

Conversion of a Non-Cancer-Selective Promoter into a Cancer-Selective Promoter.

Progression-elevated gene-3 (PEG-3) and rat growth arrest and DNA damage-inducible gene-34 (GADD34) display significant sequence homology with regulation predominantly transcriptional. The rat full-length (FL) and minimal (min) PEG-3 promoter display cancer-selective expression in rodent and human tumors, allowing for cancer-directed regulation of transgenes, viral replication and in vivo imaging of tumors and metastases in animals, whereas the FL- and min-GADD34-Prom lack cancer specificity. Min-PEG-Prom and min-GADD34-Prom have identical sequences except for two single-point mutation differences (at -260 bp and +159 bp).

New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.

The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains.

Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β.

Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples.

Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor.

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells.

Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity.

Background: The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.

Tumor cell escape from therapy-induced senescence.

H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the Senescence-Associated Secretory Phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice.

WITHDRAWN: The chromatin remodeling complex NURF localizes to gene bodies and is required for mRNA processing.

This article has been withdrawn by Aiman Alhazmi, Marissa Mack, Tiffany Rolle, Jordan Hiegel, Syed Haqqani, Nga Dao, Farheen Zaman, Nak-Kyeong Kim, Neel Scarsdale, Charles Lyons, and Joseph Landry. Some of the genome-wide data sets were flawed and were not analyzed correctly. The withdrawing authors are in the process of correcting the data sets and re-analyzing them for resubmission.

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy.

In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS) might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP) is a hallmark of TIS and may contribute to aberrant effects of cancer therapy.

Leveraging Epigenetics to Enhance the Cellular Response to Chemotherapies and Improve Tumor Immunogenicity.

Cancer chemotherapeutic drugs have greatly advanced our ability to successfully treat a variety of human malignancies. The different forms of stress produced by these agents in cancer cells result in both cell autonomous and cell nonautonomous effects. Desirable cell autonomous effects include reduced proliferative potential, cellular senescence, and cell death.

The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy.

Autophagy, a virtually uniform response to external stress such as that induced by chemotherapy and radiation, is generally considered to be cytoprotective in function, providing a foundation for multiple clinical trials designed to enhance therapeutic response via autophagy inhibition. However, this cell autonomous response can also be cytotoxic or nonprotective, with the consequence that autophagy inhibition would be counterproductive or ineffective, respectively. The non-cell autonomous function of autophagy remains quite controversial, with evidence both for and against autophagy-mediated activation of the immune system.

BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands.

Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth.

BPTF Depletion Enhances T-cell-Mediated Antitumor Immunity.

Genetic studies in fruit flies have implicated the chromatin remodeling complex nucleosome remodeling factor (NURF) in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF.

Ino80 is essential for proximal-distal axis asymmetry in part by regulating Bmp4 expression.

Background: Understanding how embryos specify asymmetric axes is a major focus of biology. While much has been done to discover signaling pathways and transcription factors important for axis specification, comparatively little is known about how epigenetic regulators are involved. Epigenetic regulators operate downstream of signaling pathways and transcription factors to promote nuclear processes, most prominently transcription.

Functional interactions between NURF and Ctcf regulate gene expression.

Gene expression frequently requires chromatin-remodeling complexes, and it is assumed that these complexes have common gene targets across cell types. Contrary to this belief, we show by genome-wide expression profiling that Bptf, an essential and unique subunit of the nucleosome-remodeling factor (NURF), predominantly regulates the expression of a unique set of genes between diverse cell types. Coincident with its functions in gene expression, we observed that Bptf is also important for regulating nucleosome occupancy at nucleosome-free regions (NFRs), many of which are located at sites occupied by the multivalent factors Ctcf and cohesin.

ATP-dependent chromatin remodeling complexes as novel targets for cancer therapy.

The progression to advanced stage cancer requires changes in many characteristics of a cell. These changes are usually initiated through spontaneous mutation. As a result of these mutations, gene expression is almost invariably altered allowing the cell to acquire tumor-promoting characteristics.

The nucleosome remodeling factor.

An essential component of the chromatin remodeling machinery is NURF (Nucleosome Remodeling Factor), the founding member of the ISWI family of chromatin remodeling complexes. In vertebrates and invertebrates alike, NURF has many important functions in chromatin biology including regulating transcription, establishing boundary elements, and promoting higher order chromatin structure. Since NURF is essential to many aspects of chromatin biology, knowledge of its function is required to fully understand how the genome is regulated.

Chromatin remodeling complex NURF regulates thymocyte maturation.

The maturation of T cells requires signaling from both cytokine and T-cell receptors to gene targets in chromatin, but how chromatin architecture influences this process is largely unknown. Here we show that thymocyte maturation post-positive selection is dependent on the nucleosome remodeling factor (NURF). Depletion of Bptf (bromodomain PHD finger transcription factor), the largest NURF subunit, in conditional mouse mutants results in developmental arrest beyond the CD4(+) CD8(int) stage without affecting cellular proliferation, cellular apoptosis, or coreceptor gene expression.