Abstract 2769: A squalene epoxidase-cholesterolaxis drives colorectal cancer progression and metastatic dissemination

Abstract

Abstract Links between cholesterol and cancer are well-documented, but the mechanisms remain unclear. Squalene epoxidase (SQLE), a key enzyme in cholesterol biosynthesis degraded by excess cholesterol, is suggested as a proto-oncogene. Paradoxically, we found reduced SQLE in aggressive colorectal cancer (CRC); low SQLE being associated with a shortened survival of CRC patients. This was confirmed in a spontaneous CRC metastasis mouse model where SL-15 reduction, by either a high-cholesterol regimen or genetic knockdown, strikingly promotes CRC aggressiveness through the production of migratory cancer stem cells. Experiments in CRC cell-lines demonstrated that SQLE reduction helps overcome constraints for malignant transformation. Specifically, we uncovered a surprising interaction of SQLE with GSK3β and p53. Depletion of SQLE disrupted the GSK3β/p53 complex, resulting in a metastatic phenotype. Our findings provide mechanistic insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC progression and potentially a biomarker for risk assessment. Citation Format: Soo Young Jun, Andrew J. Brown, Ji-Yong Yoon, Jeong-Ju Lee, Ngee Kiat Chua, Jin OK Yang, Ju-Sik Min, Insu Jang, Su-Jin Jeon, Min-Hyuk Choi, Tae-Ik Choi, Cheol-Hee Kim, Nam-Soon Kim. A squalene epoxidase-cholesterolaxis drives colorectal cancer progression and metastatic dissemination [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 2769.