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Editor | Xi The latest cancer statistics show that prostate cancer ranks first in the global male tumor incidence
.
Although its five-year survival rate is as high as 98%, the number of deaths from prostate cancer still accounts for 11% of all male malignant tumor deaths
.
The main cause of death from prostate cancer is that some patients develop metastatic castration-resistant prostate cancer (mCRPC) after receiving castration therapy
.
Current research shows that the abnormal function of androgen receptor signaling plays a key role in the occurrence and development of prostate cancer
.
Therefore, the androgen receptor signaling pathway is a molecular mechanism that is abnormally activated during the occurrence and development of prostate cancer, and how to effectively inhibit metastatic castration therapy to resist the activity of the androgen receptor signaling pathway in prostate cancer is the current field of prostate cancer research.
The key points and difficulties
.
SWI/SNF chromatin remodeling complex (SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex) is a highly conserved, ATP-dependent, multi-subunit chromatin structure regulation complex in the evolutionary process
.
The main biological function of the SWI/SNF chromatin remodeling complex is to change and remodel the interaction between the histones and DNA of the nucleosome by using its ATPase subunits (BRM and BRG1) to hydrolyze ATP.
The degree of openness of chromatin in specific regions of the genome, thereby regulating gene expression
.
New research shows that the total mutation frequency of each subunit coding gene in the SWI/SNF chromatin remodeling complex in tumors is as high as about 20%.
These mutations may change the activity of coding subunits and the function of the entire complex, thereby Affect tumor occurrence and development
.
On December 22, 2021, Dr.
Arul M.
Chinnaiyan’s team from the University of Michigan Center for Translational Pathology (MCTP) of the University of Michigan School of Medicine published a titled Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer in Nature Research papers
.
The study reported a protein degradation agent (AU-15330) for SWI/SNF chromatin remodeling complex ATPase developed based on protein degradation targeting chimera technology (proteolysis targeting chimera, PROTAC), and found that AU-15330 can By inhibiting the chromatin accessibility of the enhancer region, it efficiently and selectively inhibits the growth of androgen receptor-dependent prostate cancer in vivo and in vitro
.
By comparing the frequency of somatic mutations in the genes encoding each subunit in 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 treatments resist prostate cancer The frequency of somatic mutations in the genes encoding the subunits of the SWI/SNF chromatin remodeling complex is significantly lower than that of other common malignancies, which suggests that the occurrence and development of prostate cancer may depend on the wild-type SWI/SNF chromatin remodeling complex.
Function
.
Through cooperation with Aurigene Discovery Technologies Ltd, the two parties jointly developed a protein degradation targeted chimera technology-based SWI/SNF chromatin remodeling complex ATPase protein degradation agent (AU-15330), and used this to study SWI/SNF The biological function of chromatin remodeling complex in prostate cancer
.
Experiments have shown that AU-15330 is an efficient and specific protein degrading agent that targets the ATPase subunit of the SWI/SNF chromatin remodeling complex.
It can induce target proteins in a variety of normal and prostate cancer cells, including prostate cancer cells.
Tumor cells are rapidly degraded through the ubiquitin-proteasome pathway
.
Screening over 70 tumor cell lines from 14 different tumor types found that AU-15330 can efficiently and selectively inhibit the proliferation of androgen receptor-positive prostate cancer cell lines
.
Furthermore, through the integrated analysis of ATAC-seq, ChIP-seq and RNA-seq experimental data, it is found that AU-15330 rapidly reduces some regions of the prostate cell genome (especially enhancers) by degrading the ATPase subunit of the SWI/SNF chromatin remodeling complex The degree of chromatin openness prevents multiple transcription factors (such as androgen receptor (AR) and androgen receptor cofactors FOXA1 and ERG) from binding to the cis-acting elements of the enhancer region of its target gene, thereby significantly inhibiting The activity of multiple abnormal activation signaling pathways (such as androgen receptor and Myc signaling pathway) in prostate cancer cells
.
More interestingly, in metastatic castration therapy to resist prostate cancer cells, many transcription factors closely related to prostate cancer, including androgen receptors, often present supra-physiologic levels.
High expression status, and new research suggests that this phenomenon is closely related to the progression of primary prostate cancer to metastatic castration therapy to resist prostate cancer
.
Through ChIP-seq analysis of the distribution of H3K27Ac in prostate cancer cells, it was found that the superphysiologically high expression of transcription factors such as AR, FOXA1, ERG and c-Myc are closely related to the gain-of-function of its neighboring super enhancers.
Related
.
In this study, through HiChIP-seq (H3K4Me3 and H3K27Ac) experiments, it was found that AU-15330 can reduce the expression of transcription factors such as AR, FOXA1 and Myc to At normal physiological levels, AU-15330 can synergistically inhibit the abnormally activated signaling pathways in prostate cancer cells at the two levels of cis-acting elements and trans-acting factors
.
Finally, Dr.
Arul M.
Chinnaiyan’s team systematically evaluated the safety and effectiveness of AU-15330 in an in vivo model of castration-resistant prostate cancer
.
In terms of effectiveness, AU-15330 alone can effectively inhibit the tumor growth of prostate cancer, and when used in combination with the androgen receptor antagonist Enzalutamide, it can significantly induce the regression of castration-resistant prostate cancer
.
In terms of safety, male mice tolerate AU-15330 well, and have no significant toxicity to the hematopoietic system, gastrointestinal tract and reproductive system
.
In summary, this study reports the protein degradation agent of the specific SWI/SNF chromatin remodeling complex ATPase, AU-15330, developed based on protein degradation targeted chimera technology
.
In vitro and in vivo experiments have shown that AU-15330 can inhibit the function of the SWI/SNF chromatin remodeling complex by inducing the degradation of the target protein, and selectively induce the heterochromatinization of the enhancer region in the genome.
The two levels of formula-acting elements and trans-acting factors synergistically inhibit the abnormal activation of signal pathways in prostate cancer cells
.
This study shows that the specific degradation of SWI/SNF chromatin remodeling complex ATPase may be a new epigenetic treatment strategy for prostate cancer
.
Dr.
Lanbo Xiao, Dr.
Abhijit Parolia, and Dr.
Yuanyuan Qiao from 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
.
This work was also strongly supported by the team of Aurigene Discovery Technologies Ltd, Dovetail Genomics and Dr.
Yuzhuo Wang from the University of British Columbia
.
The University of Michigan Center for Translational Pathology (Michigan Center for Translational Pathology, MCTP) was founded and led by Dr.
Arul M.
Chinnaiyan in 2007 and is an independent cancer research center affiliated with the University of Michigan School of Medicine (center website: https://www.
pathology.
med.
umich.
edu/mctp)
.
Arul M.
Chinnaiyan is the titled professor of SP Hicks in the Department of Pathology, University of Michigan School of Medicine, a professor in the Department of Urology, a Howard Hughes Medical Institute Investigator (Howard Hughes Medical Institute Investigator), a member of the American Academy of Sciences, Cancer Cell, Cancer Discovery, etc.
Member of the editorial board of a well-known academic journal
.
At present, the Center for Translational Pathology at the University of Michigan focuses on prostate cancer, kidney cancer, multiple myeloma, and pancreatic cancer.
It uses genomics, functional genomics, immunology, bioinformatics, proteomics, and pathology.
Disciplinary research methods to systematically study the molecular mechanism of the occurrence and development of malignant tumors, and use this to develop new tumor-targeted treatments and new diagnostic strategies
.
Here, the Center for Translational Pathology of the University of Michigan sincerely invites outstanding young researchers with relevant research backgrounds in tumor biology and bioinformatics to join the Center for Translational Pathology of the University of Michigan.
Interested parties are invited to submit your resume and recommendations Send personal information to arul@med.
umich.
edu or xhcao@med.
umich.
edu
.
Original link: https:// Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, the author owns all Legal rights, offenders must be investigated
.
.
Although its five-year survival rate is as high as 98%, the number of deaths from prostate cancer still accounts for 11% of all male malignant tumor deaths
.
The main cause of death from prostate cancer is that some patients develop metastatic castration-resistant prostate cancer (mCRPC) after receiving castration therapy
.
Current research shows that the abnormal function of androgen receptor signaling plays a key role in the occurrence and development of prostate cancer
.
Therefore, the androgen receptor signaling pathway is a molecular mechanism that is abnormally activated during the occurrence and development of prostate cancer, and how to effectively inhibit metastatic castration therapy to resist the activity of the androgen receptor signaling pathway in prostate cancer is the current field of prostate cancer research.
The key points and difficulties
.
SWI/SNF chromatin remodeling complex (SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex) is a highly conserved, ATP-dependent, multi-subunit chromatin structure regulation complex in the evolutionary process
.
The main biological function of the SWI/SNF chromatin remodeling complex is to change and remodel the interaction between the histones and DNA of the nucleosome by using its ATPase subunits (BRM and BRG1) to hydrolyze ATP.
The degree of openness of chromatin in specific regions of the genome, thereby regulating gene expression
.
New research shows that the total mutation frequency of each subunit coding gene in the SWI/SNF chromatin remodeling complex in tumors is as high as about 20%.
These mutations may change the activity of coding subunits and the function of the entire complex, thereby Affect tumor occurrence and development
.
On December 22, 2021, Dr.
Arul M.
Chinnaiyan’s team from the University of Michigan Center for Translational Pathology (MCTP) of the University of Michigan School of Medicine published a titled Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer in Nature Research papers
.
The study reported a protein degradation agent (AU-15330) for SWI/SNF chromatin remodeling complex ATPase developed based on protein degradation targeting chimera technology (proteolysis targeting chimera, PROTAC), and found that AU-15330 can By inhibiting the chromatin accessibility of the enhancer region, it efficiently and selectively inhibits the growth of androgen receptor-dependent prostate cancer in vivo and in vitro
.
By comparing the frequency of somatic mutations in the genes encoding each subunit in 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 treatments resist prostate cancer The frequency of somatic mutations in the genes encoding the subunits of the SWI/SNF chromatin remodeling complex is significantly lower than that of other common malignancies, which suggests that the occurrence and development of prostate cancer may depend on the wild-type SWI/SNF chromatin remodeling complex.
Function
.
Through cooperation with Aurigene Discovery Technologies Ltd, the two parties jointly developed a protein degradation targeted chimera technology-based SWI/SNF chromatin remodeling complex ATPase protein degradation agent (AU-15330), and used this to study SWI/SNF The biological function of chromatin remodeling complex in prostate cancer
.
Experiments have shown that AU-15330 is an efficient and specific protein degrading agent that targets the ATPase subunit of the SWI/SNF chromatin remodeling complex.
It can induce target proteins in a variety of normal and prostate cancer cells, including prostate cancer cells.
Tumor cells are rapidly degraded through the ubiquitin-proteasome pathway
.
Screening over 70 tumor cell lines from 14 different tumor types found that AU-15330 can efficiently and selectively inhibit the proliferation of androgen receptor-positive prostate cancer cell lines
.
Furthermore, through the integrated analysis of ATAC-seq, ChIP-seq and RNA-seq experimental data, it is found that AU-15330 rapidly reduces some regions of the prostate cell genome (especially enhancers) by degrading the ATPase subunit of the SWI/SNF chromatin remodeling complex The degree of chromatin openness prevents multiple transcription factors (such as androgen receptor (AR) and androgen receptor cofactors FOXA1 and ERG) from binding to the cis-acting elements of the enhancer region of its target gene, thereby significantly inhibiting The activity of multiple abnormal activation signaling pathways (such as androgen receptor and Myc signaling pathway) in prostate cancer cells
.
More interestingly, in metastatic castration therapy to resist prostate cancer cells, many transcription factors closely related to prostate cancer, including androgen receptors, often present supra-physiologic levels.
High expression status, and new research suggests that this phenomenon is closely related to the progression of primary prostate cancer to metastatic castration therapy to resist prostate cancer
.
Through ChIP-seq analysis of the distribution of H3K27Ac in prostate cancer cells, it was found that the superphysiologically high expression of transcription factors such as AR, FOXA1, ERG and c-Myc are closely related to the gain-of-function of its neighboring super enhancers.
Related
.
In this study, through HiChIP-seq (H3K4Me3 and H3K27Ac) experiments, it was found that AU-15330 can reduce the expression of transcription factors such as AR, FOXA1 and Myc to At normal physiological levels, AU-15330 can synergistically inhibit the abnormally activated signaling pathways in prostate cancer cells at the two levels of cis-acting elements and trans-acting factors
.
Finally, Dr.
Arul M.
Chinnaiyan’s team systematically evaluated the safety and effectiveness of AU-15330 in an in vivo model of castration-resistant prostate cancer
.
In terms of effectiveness, AU-15330 alone can effectively inhibit the tumor growth of prostate cancer, and when used in combination with the androgen receptor antagonist Enzalutamide, it can significantly induce the regression of castration-resistant prostate cancer
.
In terms of safety, male mice tolerate AU-15330 well, and have no significant toxicity to the hematopoietic system, gastrointestinal tract and reproductive system
.
In summary, this study reports the protein degradation agent of the specific SWI/SNF chromatin remodeling complex ATPase, AU-15330, developed based on protein degradation targeted chimera technology
.
In vitro and in vivo experiments have shown that AU-15330 can inhibit the function of the SWI/SNF chromatin remodeling complex by inducing the degradation of the target protein, and selectively induce the heterochromatinization of the enhancer region in the genome.
The two levels of formula-acting elements and trans-acting factors synergistically inhibit the abnormal activation of signal pathways in prostate cancer cells
.
This study shows that the specific degradation of SWI/SNF chromatin remodeling complex ATPase may be a new epigenetic treatment strategy for prostate cancer
.
Dr.
Lanbo Xiao, Dr.
Abhijit Parolia, and Dr.
Yuanyuan Qiao from 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
.
This work was also strongly supported by the team of Aurigene Discovery Technologies Ltd, Dovetail Genomics and Dr.
Yuzhuo Wang from the University of British Columbia
.
The University of Michigan Center for Translational Pathology (Michigan Center for Translational Pathology, MCTP) was founded and led by Dr.
Arul M.
Chinnaiyan in 2007 and is an independent cancer research center affiliated with the University of Michigan School of Medicine (center website: https://www.
pathology.
med.
umich.
edu/mctp)
.
Arul M.
Chinnaiyan is the titled professor of SP Hicks in the Department of Pathology, University of Michigan School of Medicine, a professor in the Department of Urology, a Howard Hughes Medical Institute Investigator (Howard Hughes Medical Institute Investigator), a member of the American Academy of Sciences, Cancer Cell, Cancer Discovery, etc.
Member of the editorial board of a well-known academic journal
.
At present, the Center for Translational Pathology at the University of Michigan focuses on prostate cancer, kidney cancer, multiple myeloma, and pancreatic cancer.
It uses genomics, functional genomics, immunology, bioinformatics, proteomics, and pathology.
Disciplinary research methods to systematically study the molecular mechanism of the occurrence and development of malignant tumors, and use this to develop new tumor-targeted treatments and new diagnostic strategies
.
Here, the Center for Translational Pathology of the University of Michigan sincerely invites outstanding young researchers with relevant research backgrounds in tumor biology and bioinformatics to join the Center for Translational Pathology of the University of Michigan.
Interested parties are invited to submit your resume and recommendations Send personal information to arul@med.
umich.
edu or xhcao@med.
umich.
edu
.
Original link: https:// Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, the author owns all Legal rights, offenders must be investigated
.
