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; Ronald A. DePinho

doi:10.1038/s41586-023-06254-7

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 ShangDenise J. Spring, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	632-639
Number of pages	8
Journal	Nature
Volume	619
Issue number	7970
DOIs	https://doi.org/10.1038/s41586-023-06254-7
State	Published - Jul 20 2023

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Li, J., Lan, Z., Liao, W., Horner, J. W., Xu, X., Liu, J., Yoshihama, Y., Jiang, S., Shim, H. S., Slotnik, M., LaBella, K. A., Wu, C. J., Dunner, K., Hsu, W. H., Lee, R., Khanduri, I., Terranova, C., Akdemir, K., Chakravarti, D., ... DePinho, R. A. (2023). Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature, 619(7970), 632-639. https://doi.org/10.1038/s41586-023-06254-7

Li, J, Lan, Z, Liao, W, Horner, JW, Xu, X, Liu, J, Yoshihama, Y, Jiang, S, Shim, HS, Slotnik, M, LaBella, KA, Wu, CJ, Dunner, K, Hsu, WH, Lee, R, Khanduri, I, Terranova, C , Akdemir, K, Chakravarti, D, Shang, X, Spring, DJ, Wang, YA & DePinho, RA 2023, 'Histone demethylase KDM5D upregulation drives sex differences in colon cancer', Nature, vol. 619, no. 7970, pp. 632-639. https://doi.org/10.1038/s41586-023-06254-7

@article{489f138923d542f99864dd321fcfe462,

title = "Histone demethylase KDM5D upregulation drives sex differences in colon cancer",

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 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 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.",

author = "Jiexi Li and Zhengdao Lan and Wenting Liao and Horner, {James W.} and Xueping Xu and Jielin Liu and Yohei Yoshihama and Shan Jiang and Shim, {Hong Seok} and Max Slotnik and LaBella, {Kyle A.} and Wu, {Chang Jiun} and Kenneth Dunner and Hsu, {Wen Hao} and Rumi Lee and Isha Khanduri and Christopher Terranova and Kadir Akdemir and Deepavali Chakravarti and Xiaoying Shang and Spring, {Denise J.} and Wang, {Y. Alan} and DePinho, {Ronald A.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = jul,

day = "20",

doi = "10.1038/s41586-023-06254-7",

language = "English (US)",

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pages = "632--639",

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T1 - Histone demethylase KDM5D upregulation drives sex differences in colon cancer

AU - Li, Jiexi

AU - Lan, Zhengdao

AU - Liao, Wenting

AU - Horner, James W.

AU - Xu, Xueping

AU - Liu, Jielin

AU - Yoshihama, Yohei

AU - Jiang, Shan

AU - Shim, Hong Seok

AU - Slotnik, Max

AU - LaBella, Kyle A.

AU - Wu, Chang Jiun

AU - Dunner, Kenneth

AU - Hsu, Wen Hao

AU - Lee, Rumi

AU - Khanduri, Isha

AU - Terranova, Christopher

AU - Akdemir, Kadir

AU - Chakravarti, Deepavali

AU - Shang, Xiaoying

AU - Spring, Denise J.

AU - Wang, Y. Alan

AU - DePinho, Ronald A.

PY - 2023/7/20

Y1 - 2023/7/20

N2 - 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 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.

AB - 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 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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Histone demethylase KDM5D upregulation drives sex differences in colon cancer

Abstract

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