Squalene epoxidase/SQLE is a candidate target for treatment of colorectal cancers with mutation and elevated c- expression.

Elevated expression of c-MYC and inactivation of represent two of the most common alterations in colorectal cancer (CRC). However, c-MYC and defective p53 are difficult to target therapeutically. Therefore, effectors downstream of both c-MYC and p53 may represent attractive, alternative targets for cancer treatment. In a bioinformatics screen we identified Squalene epoxidase/SQLE as a candidate therapeutic target that appeared to be especially relevant for cell survival in CRCs, which display elevated c-MYC expression and loss of p53 function. SQLE is a rate-limiting enzyme in the cholesterol synthesis. Here, we show that p53 supresses SQLE expression, cholesterol levels, and cell viability via the induction of , which directly targets . Furthermore, c-MYC induced expression directly and via its target gene . The transcription factor AP4/TFAP4 directly induced expression and cholesterol levels, whereas inactivation of resulted in decreased expression and caused resistance to Terbinafine, an inhibitor of SQLE. Inhibition of SQLE decreased viability of CRC cells. This effect was enhanced in CRCs cells with inactivation and/or enhanced c-MYC/AP4 expression. Altogether, our results demonstrate that SQLE represents a vulnerability for CRCs with inactivation and elevated c-MYC activity.

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