Histone demethylase KDM5D upregulation drives sex differences in colon cancer

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 Akdemir, Deepavali Chakravarti, Xiaoying Shang, Denise J. Spring, Y. Alan Wang and Ronald A. DePinho ()
Additional contact information
Jiexi Li: The University of Texas MD Anderson Cancer Center
Zhengdao Lan: The University of Texas MD Anderson Cancer Center
Wenting Liao: The University of Texas MD Anderson Cancer Center
James W. Horner: The University of Texas MD Anderson Cancer Center
Xueping Xu: The University of Texas MD Anderson Cancer Center
Jielin Liu: The University of Texas MD Anderson Cancer Center
Yohei Yoshihama: The University of Texas MD Anderson Cancer Center
Shan Jiang: The University of Texas MD Anderson Cancer Center
Hong Seok Shim: The University of Texas MD Anderson Cancer Center
Max Slotnik: The University of Texas MD Anderson Cancer Center
Kyle A. LaBella: The University of Texas MD Anderson Cancer Center
Chang-Jiun Wu: The University of Texas MD Anderson Cancer Center
Kenneth Dunner: The University of Texas MD Anderson Cancer Center
Wen-Hao Hsu: The University of Texas MD Anderson Cancer Center
Rumi Lee: The University of Texas MD Anderson Cancer Center
Isha Khanduri: The University of Texas MD Anderson Cancer Center
Christopher Terranova: The University of Texas MD Anderson Cancer Center
Kadir Akdemir: The University of Texas MD Anderson Cancer Center
Deepavali Chakravarti: The University of Texas MD Anderson Cancer Center
Xiaoying Shang: The University of Texas MD Anderson Cancer Center
Denise J. Spring: The University of Texas MD Anderson Cancer Center
Y. Alan Wang: The University of Texas MD Anderson Cancer Center
Ronald A. DePinho: The University of Texas MD Anderson Cancer Center

Nature, 2023, vol. 619, issue 7970, 632-639

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06254-7

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