1. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
Kouhei Shimizu, Mark A Rubin, Shangqian Wang, Qing Zhong, Hiroyuki Inuzuka, Levi A Garraway, Andrew H Beck, Ling Huang, Wenyi Wei, Liewei Wang, Xiaoning Li, Jianping Guo, Ting Chen, Wei Zhang, Francisco Beca, Jinfang Zhang, Xiangpeng Dai, Lorenz Buser, Peter J Wild, Kwok-Kin Wong, James E Bradner, Yu Chen, Pengda Liu, Jun Qi, Jiaoti Huang, Senthil K Muthuswamy, Mirjam Blattner, Christopher E Barbieri, Dennis L Buckley, Shengwu Liu, Wenjian Gan, Divya Vasudevan Nat Med . 2017 Sep;23(9):1063-1071. doi: 10.1038/nm.4378.
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOPearmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
2. Suppression of inflammation by a synthetic histone mimic
Charles M Rice, Alexander Tarakhovsky, Jose M Lora, Hervé Coste, Kate L Jeffrey, Paul Wilson, Julia White, Jorge Kirilovsky, Scott Dewell, Rohit Chandwani, Rab K Prinjha, Chun-Wa Chung, Kevin Lee, Ivan Marazzi, Edwige Nicodeme, Uwe Schaefer, Soren Beinke Nature . 2010 Dec 23;468(7327):1119-23. doi: 10.1038/nature09589.
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
3. Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention
Michal Schwartz, Aharon Nachshon, Mark R Wills, Sarah E Jackson, Emma L Poole, David F Tough, John H Sinclair, Rab K Prinjha, Ian J Groves, Batsheva Rozman Proc Natl Acad Sci U S A . 2021 Mar 2;118(9):e2023025118. doi: 10.1073/pnas.2023025118.
Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.
CAS No.: 1300019-38-8
