Y Chromosome Gene Kdm5D Epigenetically Drives Sex Differences In Colorectal Cancer

<p>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 KRAS^G12D and conditional null alleles of <em>Apc</em> and <em>Trp53</em> 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 <em>KDM5D</em> as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor in cancer cells. 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 <em>Kdm5d</em> 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 <em>Kdm5d </em>transgene to provide constitutive <em>Kdm5d</em> expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors <em>in vivo</em>. In addition, upregulated <em>KDM5D</em> expression in CD8+ T cells contributes to a suppressive immune response in men. Thus, upregulation of Y chromosome <em>KDM5D</em> in cancer cells and immune cells collaboratively contributes to the sex differences in CRC via its disruption of cancer cell adhesion properties and regulation of tumor immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Li, Jiexi
• <p>https://orcid.org/0000-0003-1508-5732</p>

Contributors dc:contributor

• Ronald A. DePinho, M.D.
• Scott Kopetz, M.D., Ph.D.
• Guillermina (Gigi) Lozano, Ph.D.

• Colorectal Cancer
• Epigenetics
• Sex Differences
• Metastasis
• Tumor Microenvironment
• CD8+ T Cells
• Epithelial-Mesenchymal Transition
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1257

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2315