Histone demethylase KDM5D upregulation drives sex differences in colon cancer
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ABSTRACT:
PROVIDER: PRJNA972008 | ENA |
REPOSITORIES: ENA
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Project description:Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and MHC class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
2023-05-13 | GSE232458 | GEO
Project description:Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and MHC class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
2023-05-13 | GSE232457 | GEO
Project description:Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and MHC class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
2023-05-13 | GSE232456 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-12 | GSE232459 | GEO
Project description:Sex differences in RBM20 cardiomyopathy
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Project description:Sex-related differences in Alzheimer’s disease
| PRJNA839023 | ENA
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085874 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085884 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085889 | GNPS