Abstract LB-125: KDM5D as a novel gender-specific gene target for metastatic colorectal cancer

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Abstract Male colorectal cancer (CRC) patients have higher rates of incidence, mortality and poorer responsiveness to therapy compared to female patients, making it critical to identify the significant factors contributing to the gender differences and to explore gender-specific therapeutic interventions. Here, combining unbiased expression profiling and xenograft mouse model discovered the Y chromosome gene KDM5D as a male-specific pro-metastasis gene and its upregulation contributes to poorer survival in both human and mouse. Knockout of Kdm5d in male metastatic CRC cell lines aborted the liver metastasis occurrence while overexpressing Kdm5d in female primary CRC cell lines enabled their metastasis potential. Mechanistically, ChIP-seq analysis showed KDM5D primarily works as a demethylase for histone modification H3K4me2/3, downregulating metastasis-suppressing genes. KDM5D also regulates the chromosome accessibility, indicated by H3K27Ac level change and validated with ATAC-seq. Kras G12D mutation regulates Kdm5d expression and is correlated with poorer survival in male mice, which is validated in silico in human CRC data in TCGA. KDM5 family inhibitor "compound 48" showed significant power to inhibit the migration capability of human metastatic CRC cell line LoVo. This study provided a new understanding of the effect of gender on CRC and a novel gender specific therapeutic target for metastatic CRC. Citation Format: Jiexi Li, Zhengdao Lan, Alan Y. Wang, Ron DePinho. KDM5D as a novel gender-specific gene target for metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-125.