c-MYC的高表达和p53的失活是结直肠癌（CRC）中两种最常见的变化。然而，c-MYC和缺陷的p53在治疗上很难靶向。因此，c-MYC和p53下游体效应因子可能代表肿瘤治疗中具有吸引力的替代靶点。在生物信息学筛选中，我们发现角鲨烯环氧化酶/SQLE作为一个候选治疗靶点，对于表达高水平c-MYC和失活的p53功能的CRC细胞的存活尤其相关。SQLE是胆固醇合成中的限速酶。在这里，我们展示了p53通过诱导miR-205直接抑制SQLE的表达、胆固醇水平和细胞存活。此外，c-MYC通过其靶基因AP4直接诱导SQLE的表达。转录因子AP4/TFAP4直接诱导SQLE的表达和胆固醇水平，而AP4的失活导致SQLE的表达下降并引起Terbinafine（SQLE的抑制剂）的耐药性。抑制SQLE降低了CRC细胞的存活能力。在p53失活和/或c-MYC/AP4表达增强的CRC细胞中，这种效应被增强。总之，我们的研究结果表明，SQLE代表了p53失活和c-MYC活性升高的CRC的一个易感性点。©该作者。

Elevated expression of c-MYC and inactivation of p53 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 miR-205, which directly targets SQLE. Furthermore, c-MYC induced SQLE expression directly and via its target gene AP4. The transcription factor AP4/TFAP4 directly induced SQLE expression and cholesterol levels, whereas inactivation of AP4 resulted in decreased SQLE 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 p53 inactivation and/or enhanced c-MYC/AP4 expression. Altogether, our results demonstrate that SQLE represents a vulnerability for CRCs with p53 inactivation and elevated c-MYC activity.© The author(s).