Histone demethylase KDM5D upregulation drives sex differences in colon cancer

克拉斯 生物 癌症研究 结直肠癌 癌症 转录组 下调和上调 遗传学 基因 基因表达
作者
Jiexi Li,Zhengdao Lan,Wenting Liao,James W. Horner,Xueping Xu,Jielin Liu,Yohei Yoshihama,Shan Jiang,Hong Seok Shim,Max Slotnik,Kyle A. LaBella,Chang-Jiun Wu,Kenneth Dunner,Wen-Hao Hsu,Rumi Lee,Isha Khanduri,Christopher Terranova,Kadir C. Akdemir,Deepavali Chakravarti,Xiaoying Shang,Denise J. Spring,Y. Alan Wang,Ronald A. DePinho
出处
期刊:Nature [Springer Nature]
卷期号:619 (7970): 632-639 被引量:14
标识
DOI:10.1038/s41586-023-06254-7
摘要

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.
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