Deciphering the Mechanisms of Multiple Myeloma Tumor Driving Factor Whsc1 in Kras Mutated Colon Cancer Progression and Investigate the Whsc1 Targeting Combination Therapy

Despite the great improvement of therapeutic strategies for colon cancer therapy in the past decades, the survival rate of late staged or metastatic colon cancer patients remains low. Especially, there are not many effective treatment options for around 30% of patients who harbor KRAS gene mutations. Therefore, investigation on regulatory mechanisms of colon cancer progression and identification of novel molecular targets for colon cancer therapy is critical. WHSC1, well known as a multiple myeloma tumor driving factor, was identified in our previous microarray analysis in which WHSC1 was suggested to be involved in colon cancer oncogenesis. We further investigated samples from colon cancer patients, and established the association between high WHSC1 expression and late staged colon cancer parameter. We have established a CRISPR/Cas9-mediated WHSC1 knockout stable cell line for this study. Our preliminary data from KRAS mutated colon cancer cells suggested a promoting role of WHSC1 in the disease progression and a potential involvement of WHSC1 in colon cancer drug resistance. Moreover, there was synergic effect of colon cancer cells inhibition with WHSC1 knockout plus 5FU treatment. The main goal of this proposal is to clarify the oncogenic regulatory mechanisms of WHSC1 in colon cancer, thereby identify WHSC1 as a novel molecular target for future KRAS mutant colon cancer therapy. There are four aims within our proposal. First, we plan to evaluate the impacts of WHSC1 on cell proliferation and metastasis capacity of colon cancer. Next, we will investigate the involvement of WHSC1 in modulating epithelial-mesenchymal transition (EMT) in colon cancer. Then, we plan to investigate the molecular regulation of WHSC1 and HIC2 in 5FU and Oxaliplatin drug resistance. Finally, we will examine the role of WHSC1 in tumor growth in the mice model. Also, we will investigate the combination therapy with WHSC1 knockout and 5-FU/Oxaliplatin in the mice model. The result from the project will not only elucidate the role of WHSC1 in tumorigenesis of colon cancer, but also provide crucial information for the future development of KRAS mutant colon cancer therapy.