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 | GSE232456 | 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 and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which 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 tumour suppressors (designated iKAP)2, 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 upregulated 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 major histocompatibility complex 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 showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
| S-EPMC10529424 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-12 | GSE232459 | GEO
Project description:Mammalian sex differences are determined by the X and Y chromosomes. Ancestral homologous genes on the sex chromosomes, termed X-Y gene pairs, have been predicted to drive sex differences. However, among the five X-Y gene pairs conserved across eutherians, which pairs drive sex-biased gene expression have remained undefined. Here, we investigate the roles of the X-Y gene pair Kdm5c-Kdm5d in regulating sex-biased gene expression independently of sex hormones using pluripotent mouse embryonic stem cells (ESCs) as a model. Wild-type (WT) XX female and WT XY male ESCs significantly differ in the expression of approximately 4% of all expressed genes, classified as female- or male-biased. Loss of Kdm5c in female ESCs results in the downregulation of female-biased genes. In contrast, loss of either Kdm5c or Kdm5d in male ESCs results in the upregulation of female-biased genes and downregulation of male-biased genes, effectively neutralizing sex-biased gene expression. In male ESCs, most sex-biased genes change in expression in a similar direction upon loss of Kdm5c or Kdm5d. However, Kdm5c loss dysregulates a greater number of sex-biased genes relative to Kdm5d loss in male ESCs. Remarkably, in female ESCs ectopic Kdm5d expression is sufficient to drive a sex-biased gene expression pattern similar to that of WT male ESCs. Taken together, these results establish Kdm5c-Kdm5d as a critical X-Y gene pair in driving sex-biased gene expression in pluripotent cells.
2024-12-13 | GSE277494 | GEO
Project description:KDM5C is commonly mutated in ccRCC tumours in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild type ccRCC cell lines caused different phenotypes and nonoverlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.
2025-01-21 | GSE284611 | GEO
Project description:KDM5C is commonly mutated in ccRCC tumours in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild type ccRCC cell lines caused different phenotypes and nonoverlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.
2025-01-21 | GSE284610 | GEO
Project description:KDM5C is commonly mutated in ccRCC tumours in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild type ccRCC cell lines caused different phenotypes and nonoverlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.
2025-01-21 | GSE284609 | GEO