Colorectal cancer (CRC) is the third leading cause of cancer death in US and is characterized by signature mutations of APC, p53, KRAS, SMAD4, among other genetic alterations. It is well established that male CRC patients have worse prognosis than that of female patients, but the underlying mechanism is largely undefined. Recent efforts in large scale whole genome and whole exome sequencing of metastatic CRC samples have not identified novel metastatic promoting genes suggesting metastatic progression may be largely regulated by epigenetic mechanisms. We have recently established an inducible oncogenic KRas metastatic CRC animal model and employing this model we have identified a male specific Y-chromosome residing gene- KDM5D, as a key regulator of CRC metastatic progression. This discovery is exciting as it connects sex biased CRC progression with an epigenetic regulator that is druggble. In this proposal, we will employ both in vitro and animal models to elucidate the function of KDM5D in CRC progression and define novel therapeutic approach targeting CRC metastasis. To achieve this goal, we propose the following specific aims. 1. Elucidate the role of KDM5D in CRC progression; 2. Define Kras mediated KDM5D upregulation in CRC and KDM5D downstream targets in promoting metastasis; 3. Mechanistic understanding of KDM5D promotion of metastasis in vivo.

The goal of this proposal is to elucidate the mechanisms of male specific gene KDM5D in promoting colorectal cancer metastasis using both in vitro and animal models. KDM5D upstream and downstream effectors' function will be determined. The potential of KDM5D as a therapeutic target will be determined using mouse models.