Histone demethylase KDM5D upregulation drives sex differences in colon cancer

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 hormones 1 . Such sex differences are particularly prominent in colorectal cancer (CRC) in whi...

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Published in:	Nature (London) Vol. 619; no. 7970; pp. 632 - 639
Main Authors:	Li, Jiexi, Lan, Zhengdao, Liao, Wenting, Horner, James W., Xu, Xueping, Liu, Jielin, Yoshihama, Yohei, Jiang, Shan, Shim, Hong Seok, Slotnik, Max, LaBella, Kyle A., Wu, Chang-Jiun, Dunner, Kenneth, Hsu, Wen-Hao, Lee, Rumi, Khanduri, Isha, Terranova, Christopher, Akdemir, Kadir, Chakravarti, Deepavali, Shang, Xiaoying, Spring, Denise J., Wang, Y. Alan, DePinho, Ronald A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 20-07-2023 Nature Publishing Group
Subjects:	13/51 14/19 14/28 38/15 631/67/1504/1885 631/67/322 631/67/327 631/67/68/2486 64/60 82/51 82/58 Adenomatous polyposis coli Animals Antigen-presenting cells CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell adhesion Chromatin Clinical outcomes Colon cancer Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Disease Models, Animal Epithelial cells Epithelium Evolution Female Females Gender differences Gene expression Histone Demethylases - genetics Histone Demethylases - metabolism Histones Humanities and Social Sciences Humans Invasiveness K-Ras protein Lymphocytes Lymphocytes T Major histocompatibility complex Male Males Men Metastases Metastasis Mice Mice, Transgenic Minor Histocompatibility Antigens - genetics Minor Histocompatibility Antigens - metabolism Mortality multidisciplinary Mutants Mutation Risk management Science Science (multidisciplinary) Sex Characteristics Sex differences Stat4 protein Suppressors Survival analysis Transcription activation Transcriptomes Transcriptomics Transgenes Tumors Up-Regulation X chromosomes Y chromosomes
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Summary:	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 hormones 1 . 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 KRAS G12D 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. A murine colorectal cancer (CRC) model shows that mutant KRAS-STAT4-mediated upregulation of Y chromosome KDM5D contributes to the sex differences in KRAS-mutant CRC, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS-mutant CRC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J.L., Y.A.W. and R.A.D. designed the project and analyzed the data; Z.L. established the iKAP primary and metastatic cell lines, conducted the in vivo study in nude mice and helped with the survival analysis in CRC patients; W.L. helped with tumour staging; J.W.H. and X.X. generated the iAP-KDM5D mouse model; J. Liu helped with MHC-I detection, antigen presentation assay and T cell killing assay; Y.Y. helped with immunofluorescence, confocal imaging, paracellular permeability assay and the quantitation of the tight junction integrity; S.J. maintained, monitored and recorded the health condition of the genetically engineered mice; H.S.S. helped with qPCR of FFPE tumour tissue, IP-MS and co-IP experiment; M.S. helped with immunohistochemistry; K.A.L. helped with organoid culture and engineering; C.W. analyzed the RNA-seq data and performed GSEA; K.D. performed the transmission electron microscopy and helped with the quantitation of the tight junction integrity; W.H. established the iKAP tumour organoid lines and helped with animal surgeries; R.L. helped with the luciferase reporter assay; I.K. helped with the tumour staging; C.T. and K.A. helped with the HiChIP experiment and analysis; D.C. helped with organoid culture; X.S. helped with mouse genotyping; J.L. and R.A.D. wrote the manuscript; D.J.S. edited the manuscript and reviewed data. Author Contributions
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-023-06254-7