A new strategy for epigenetic therapy of prostate cancer based on targeting SWI/SNF chromatin remodeling complex ATPase

Editor-in-Chief | Xi's latest cancer statistics data show that prostate cancer ranks first in the global male cancer incidence
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Although its five-year survival rate is as high as 98%, prostate cancer still accounts for 11% of all male cancer deaths
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The main cause of death from prostate cancer is that some patients develop metastatic castration-resistant prostate cancer (mCRPC) after receiving castration therapy
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Current studies have shown that dysfunction of androgen receptor signaling plays a key role in the occurrence and development of prostate cancer
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Therefore, the androgen receptor signaling pathway is a molecular mechanism of abnormal activation in the development of prostate cancer, and how to effectively inhibit the activity of the androgen receptor signaling pathway in metastatic castration-resistant prostate cancer is the current field of prostate cancer research.
focus and difficulty
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The SWI/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex is a class of highly conserved, ATP-dependent, multi-subunit chromatin structure regulatory complexes during evolution
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The main biological function of the SWI/SNF chromatin remodeling complex is to alter and remodel the interaction between histones and DNA of the nucleosome by utilizing the energy obtained from the hydrolysis of ATP by its ATPase subunits (BRM and BRG1), thereby affecting the The degree of chromatin opening in specific regions of the genome, thereby regulating gene expression
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Recent studies have shown that the total mutation frequency of genes encoding each subunit in the SWI/SNF chromatin remodeling complex is as high as about 20% in tumors, and these mutations may alter the activity of the encoded subunits and the function of the entire complex.
Affect tumorigenesis and development
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On December 22, 2021, the team of Dr.
Arul M.
Chinnaiyan at the Michigan Center for Translational Pathology (MCTP) at the University of Michigan School of Medicine published in Nature a report titled Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer research paper
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This study reports a protein degrader (AU-15330) targeting SWI/SNF chromatin remodeling complex ATPase developed based on proteolysis targeting chimera (PROTAC), and found that AU-15330 can Efficient and selective inhibition of androgen receptor-dependent prostate cancer growth in vivo and in vitro by inhibiting chromatin accessibility in enhancer regions
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 By comparing the frequency of somatic mutations in genes encoding each subunit of the SWI/SNF chromatin remodeling complex in prostate cancer and other tumors, Dr.
Arul M.
Chinnaiyan's team found that primary prostate and metastatic castration-resistant prostate cancer The frequency of somatic mutation in the genes encoding each subunit of the SWI/SNF chromatin remodeling complex is significantly lower than that of other common malignant tumors, suggesting that the occurrence and development of prostate cancer may depend on the wild-type SWI/SNF chromatin remodeling complex.
function
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Through cooperation with Aurigene Discovery Technologies Ltd, the two parties jointly developed a protein degrader (AU-15330) of SWI/SNF chromatin remodeling complex ATPase based on protein degradation targeting chimera technology, and used this to study SWI/SNF Biological functions of chromatin remodeling complexes in prostate cancer
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Experiments show that AU-15330 is a highly efficient and specific protein degrader targeting the ATPase subunit of the SWI/SNF chromatin remodeling complex, which can induce the target protein in a variety of normal and Rapid degradation in tumor cells via the ubiquitin-proteasome pathway
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Screened in more than 70 tumor cell lines from 14 different tumor types, AU-15330 was found to efficiently and selectively inhibit the proliferation of androgen receptor-positive prostate cancer cell lines
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Further, through the integrated analysis of ATAC-seq, ChIP-seq and RNA-seq experimental data, it was found that AU-15330 rapidly reduced some regions of the prostate cell genome (especially enhancers) by degrading the SWI/SNF chromatin remodeling complex ATPase subunit.
The degree of chromatin openness, blocking the binding of multiple transcription factors, such as the androgen receptor (AR) and the androgen receptor cofactors FOXA1 and ERG, to cis-acting elements in the enhancer regions of their target genes, thereby significantly inhibiting the Activity of multiple abnormally activated signaling pathways (such as androgen receptor and Myc signaling pathways) in prostate cancer cells
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More interestingly, in metastatic castration-resistant prostate cancer cells, multiple transcription factors closely related to prostate cancer, including the androgen receptor, often exhibit supra-physiologic levels.
High expression status, and new research suggests that this phenomenon is closely related to the evolution of primary prostate cancer to metastatic castration-resistant prostate cancer
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Analysis of the distribution of H3K27Ac in prostate cancer cells by ChIP-seq revealed that the supraphysiological high expression of transcription factors such as AR, FOXA1, ERG and c-Myc is closely related to the gain-of-function of adjacent super enhancers related
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In this study, HiChIP-seq (H3K4Me3 and H3K27Ac) experiments showed that AU-15330 could reduce the expression of transcription factors such as AR, FOXA1 and Myc by disrupting the interaction between super-enhancers and promoters of the above transcription factors.
At normal physiological levels, AU-15330 thus synergistically inhibits abnormally activated signaling pathways in prostate cancer cells at both cis-acting and trans-acting levels
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Finally, Dr.
Arul M.
Chinnaiyan's team systematically evaluated the safety and efficacy of AU-15330 in an in vivo model of castration-resistant prostate cancer
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In terms of efficacy, AU-15330 alone can effectively inhibit the tumor growth of prostate cancer, and when combined with the androgen receptor antagonist Enzalutamide (Enzalutamide) can significantly induce regression of castration-resistant prostate cancer
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In terms of safety, AU-15330 is well tolerated by male mice and has no significant toxicity to the hematopoietic system, gastrointestinal tract and reproductive system
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 In conclusion, this study reports a specific SWI/SNF chromatin remodeling complex ATPase protein degrader, AU-15330, developed based on protein degradation-targeted chimera technology
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In vitro and in vivo experiments show that AU-15330 can inhibit the function of SWI/SNF chromatin remodeling complex by inducing the degradation of target proteins, and selectively induce heterochromatinization of enhancer regions in the genome.
Synergistic inhibition of abnormally activated signaling pathways in prostate cancer cells at two levels of expression-acting elements and trans-acting factors
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This study suggests that the specific degradation of the SWI/SNF chromatin remodeling complex ATPase may be a novel epigenetic therapy strategy for prostate cancer
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Dr.
Lanbo Xiao, Dr.
Abhijit Parolia and Dr.
Yuanyuan Qiao of the Center for Translational Pathology at the University of Michigan are the co-first authors of the paper, and Dr.
Arul M.
Chinnaiyan is the corresponding author of the paper
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This work was also strongly supported by Aurigene Discovery Technologies Ltd, Dovetail Genomics, and the team of Dr.
Yuzhuo Wang at the University of British Columbia
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The Michigan Center for Translational Pathology (MCTP) is an independent tumor research center affiliated to the University of Michigan School of Medicine established and led by Dr.
Arul M.
Chinnaiyan in 2007 (center website: https://www.
pathology.
med.
umich.
edu/mctp)
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Arul M.
Chinnaiyan is SP Hicks Named Professor of the Department of Pathology, University of Michigan School of Medicine, Professor of the Department of Urology, Howard Hughes Medical Institute Investigator, Academician of the National Academy of Sciences, Cancer Cell, Cancer Discovery and other international The editorial board of famous academic journals
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Currently, the Center for Translational Pathology at the University of Michigan focuses on prostate cancer, kidney cancer, multiple myeloma, and pancreatic cancer.
Disciplinary research methods, systematically study the molecular mechanism of the occurrence and development of malignant tumors, and develop new tumor targeted therapy and diagnosis strategies.

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Here, the Center for Translational Pathology at the University of Michigan sincerely invites outstanding young researchers with research backgrounds in tumor biology and bioinformatics to join the Center for Translational Pathology at the University of Michigan.
Interested parties are welcome to send your resume and recommendation Send personal information to arul@med.
umich.
edu or xhcao@med.
umich.
edu
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