Rewiring of master transcription factor cistromes during high-grade serous ovarian cancer development
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Curated by eLife
eLife assessment
This fundamental study has successfully identified four key transcription factors (MECOM, PAX8, SOX17, and WT1) that exhibit synergistic effects and are potentially responsible for the transformation of fallopian tube secretory epithelial cells into high-grade serous 'ovarian' cancer cells. Convincing data strongly support the drawn conclusion and significantly contribute to our understanding of the etiology of this devastating cancer. The implications of this finding are substantial, as it provides valuable molecular insights that can potentially pave the way for innovative diagnostics and therapeutics in the field of gynecological oncology. Enhancing the clarity and impact of this study would be achieved through improvements in data presentation.
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Abstract
The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous ‘ovarian’ cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors in cis and trans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.
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eLife assessment
This fundamental study has successfully identified four key transcription factors (MECOM, PAX8, SOX17, and WT1) that exhibit synergistic effects and are potentially responsible for the transformation of fallopian tube secretory epithelial cells into high-grade serous 'ovarian' cancer cells. Convincing data strongly support the drawn conclusion and significantly contribute to our understanding of the etiology of this devastating cancer. The implications of this finding are substantial, as it provides valuable molecular insights that can potentially pave the way for innovative diagnostics and therapeutics in the field of gynecological oncology. Enhancing the clarity and impact of this study would be achieved through improvements in data presentation.
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Reviewer #1 (Public Review):
This manuscript describes extensive transcriptomic and epigenomic profiling for high-grade serous 'ovarian' cancer (HGSC) and its precancerous precursor the fallopian tube secretory epithelium cells (FTSEC). This study identifies MECOM, PAX8, SOX17 and WT1 as master transcription factors that regulate HGSC and FTSEC, as well as the transition from FTSEC to HGSC.
Overall, most the experiments described in the manuscript are well designed and executed. The data presented are of high quality, convincing, and in general support the conclusions made in the manuscript.
Given the complexity of the data and analysis, some clarification is needed to guide readers to better understand the results.
The definition of super enhancers should be clarified. In general, super enhancers are defined by large domains of …
Reviewer #1 (Public Review):
This manuscript describes extensive transcriptomic and epigenomic profiling for high-grade serous 'ovarian' cancer (HGSC) and its precancerous precursor the fallopian tube secretory epithelium cells (FTSEC). This study identifies MECOM, PAX8, SOX17 and WT1 as master transcription factors that regulate HGSC and FTSEC, as well as the transition from FTSEC to HGSC.
Overall, most the experiments described in the manuscript are well designed and executed. The data presented are of high quality, convincing, and in general support the conclusions made in the manuscript.
Given the complexity of the data and analysis, some clarification is needed to guide readers to better understand the results.
The definition of super enhancers should be clarified. In general, super enhancers are defined by large domains of enhancer clusters with high levels of H3K27ac, typically at least 10KB in size. The "super enhancers" presented in Figure 2 do not appear to be large clusters of enhancers.
Fig. 4D. Difficult to understand. Multiple bars seem to be represented by the same binding patterns by the four TFs. Need better description in both the text and figure legends.
"These data suggest that the antiproliferative effects of THZ1 and THZ531 in HGSC cells may be due to tumor-specific inhibition of MECOM, PAX8 and SOX17 expression by these drugs." Can the author expand the discussion on how CDK7/12 inhibitors could achieve tumor-specific inhibition of MECOM, PAX8 and SOX17?
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Reviewer #2 (Public Review):
This study found that MECOM, PAX8, SOX17, and WT1, as the main regulators of high-grade serous ovarian cancer (HGSC), their transcriptional regulation related to the super-enhancer, were reconnected in the process of tumor development. These four TFS are essential for the clonality and survival of HGSC, while the absence of PAX8 and WT1 in non-cancerous fallopian tube secretory epithelium (FTSEC) can impair the survival of cells. These four TFS are only pharmacologically inhibited by transcriptional inhibitors in HGSCs, while not in FTSECs, making them potential targets for tumor-specific therapy.
I am thrilled to see such an exciting and scientific manuscript. The results will significantly impact the basic theory of cancer occurrence and clinical applications.
However, there were some issues with the data …
Reviewer #2 (Public Review):
This study found that MECOM, PAX8, SOX17, and WT1, as the main regulators of high-grade serous ovarian cancer (HGSC), their transcriptional regulation related to the super-enhancer, were reconnected in the process of tumor development. These four TFS are essential for the clonality and survival of HGSC, while the absence of PAX8 and WT1 in non-cancerous fallopian tube secretory epithelium (FTSEC) can impair the survival of cells. These four TFS are only pharmacologically inhibited by transcriptional inhibitors in HGSCs, while not in FTSECs, making them potential targets for tumor-specific therapy.
I am thrilled to see such an exciting and scientific manuscript. The results will significantly impact the basic theory of cancer occurrence and clinical applications.
However, there were some issues with the data presentation. We hope that the author will carefully and rigorously review the data and visualization results. In addition, there is key information missing in the methods section, which does not meet the current requirements for the repeatability of scientific conclusions.
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