Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer.
2015; 75 (19): 4176-4187
Chemical profiling of the genome with anti-cancer drugs defines target specificities
NATURE CHEMICAL BIOLOGY
2015; 11 (7): 472-?
The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase IIα, respectively, whereas deletion of C9orf82 augments subsequent DSB repair. Their corresponding genes, frequently mutated or deleted in human tumors, may impact drug sensitivity, as exemplified by triple-negative breast cancer patients with diminished SWI/SNF core member expression who exhibit reduced responsiveness to chemotherapy regimens containing doxorubicin. Collectively, our work identifies genes that may predict the response of cancer patients to the broadly used topoisomerase II poisons and defines alternative pathways that could be therapeutically exploited in treatment-resistant patients. Cancer Res; 75(19); 4176-87. ©2015 AACR.
View details for DOI 10.1158/0008-5472.CAN-15-0380
View details for PubMedID 26260527
Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin
Many anticancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors additionally cause histone eviction. Here, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. The TopoI inhibitor topotecan and the TopoII inhibitor etoposide are similar in inducing DNA damage at transcriptionally active genomic regions. The anthracycline daunorubicin induces DNA breaks and evicts histones from active chromatin, thus quenching local DNA damage responses. Another anthracycline, aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.
View details for DOI 10.1038/NCHEMBIO.1811
View details for Web of Science ID 000356334600011
View details for PubMedID 25961671
Coupled for Cross-Presentation in Tumor Immunotherapy
SCIENCE TRANSLATIONAL MEDICINE
2010; 2 (44)
DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.
View details for DOI 10.1038/ncomms2921
View details for Web of Science ID 000320589900104
View details for PubMedID 23715267
Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis
JOURNAL OF IMMUNOLOGY
2009; 183 (2): 1083-1090
Antigen cross-presentation is a critical step in the elicitation of cell-mediated immune responses. Much research has been aimed at manipulating antigen cross-presentation to improve tumor immunotherapy and vaccination. In this issue of Science Translational Medicine, Saccheri et al. describe a mechanism for spurring successful antitumor responses by enhancing the transfer, to antigen-presenting cells, of tumor-specific antigens that leave the cancer cells via gap junctions induced by Salmonella infection of the melanoma tumor. Salmonella turns from foe to friend by promoting cross-presentation for strong antitumor immunity and tumor eradication.
View details for DOI 10.1126/scitranslmed.3001245
View details for Web of Science ID 000288434700002
View details for PubMedID 20702855
Gap Junction Communication between Autologous Endothelial and Tumor Cells Induce Cross-Recognition and Elimination by Specific CTL
JOURNAL OF IMMUNOLOGY
2009; 182 (5): 2654-2664
MHC class I molecules present peptides from endogenous proteins. Ags can also be presented when derived from extracellular sources in the form of apoptotic bodies. Cross-presentation of such Ags by dendritic cells is required for proper CTL responses. The fate of Ags in cells initiated for apoptosis is unclear as is the mechanism of apoptosis-derived Ag transfer into dendritic cells. Here we show that novel Ags can be generated by caspases and be presented by MHC class I molecules of apoptotic cells. Since gap junctions function until apoptotic cells remodel to form apoptotic bodies, transfer and cross-presentation of apoptotic peptides by neighboring and dendritic cells occurs. We thus define a novel phase in classical Ag presentation and cross-presentation by MHC class I molecules: presentation of Ags created by caspase activities in cells in apoptosis.
View details for DOI 10.4049/jimmunol.0900861
View details for Web of Science ID 000267812600034
View details for PubMedID 19553546
Gap junction-mediated intercellular communication in the immune system
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
2007; 94 (1-2): 207-218
Cellular interactions in the tumor stroma play a major role in cancer progression but can also induce tumor rejection. To explore the role of endothelial cells in these interactions, we used an in vitro three-dimensional collagen matrix model containing a cytotoxic T lymphocyte CTL clone (M4.48), autologous tumor cells (M4T), and an endothelial cell (M4E) line that are all derived from the same tumor. We demonstrate in this study that specific killing of the endothelial cells by the CTL clone required the autologous tumor cells and involved Ag cross-presentation. The formation of gap junctions between endothelial and tumor cells is required for antigenic peptide transfer to endothelial cells that are then recognized and eliminated by CTL. Our results indicate that gap junctions facilitate an effective CTL-mediated destruction of endothelial cells from the tumor microenvironment that may contribute to the control of tumor progression.
View details for DOI 10.4049/jimmunol.0800815
View details for Web of Science ID 000263653100014
View details for PubMedID 19234159
Immune cells are usually considered non-attached blood cells, which would exclude the formation of gap junctions. This is a misconception since many immune cells express connexin 43 (Cx43) and other connexins and are often residing in tissue. The role of gap junctions is largely ignored by immunologists as is the immune system in the field of gap junction research. Here, the current knowledge of the distribution of connexins and the function of gap junctions in the immune system is discussed. Gap junctions appear to play many roles in antibody productions and specific immune responses and may be important in sensing danger in tissue by the immune system. Gap junctions not only transfer electrical and metabolical but also immunological information in the form of peptides for a process called cross-presentation. This is essential for proper immune responses to viruses and possibly tumours. Until now only 40 research papers on gap junctions in the immune system appeared and this will almost certainly expand with the increased mutual interest between the fields of immunology and gap junction research.
View details for DOI 10.1016/j.bpiomolbio.2007.03.008
View details for Web of Science ID 000247390000011
View details for PubMedID 17467043