Squalene epoxidase/SQLE is a candidate target for treatment of colorectal cancers with p53 mutation and elevated c-MYC expression

Abstract

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.

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

“…SQLE is the second key enzyme in cholesterol biosynthesis and catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene. The correlation between the high expression of SQLE and the poor prognosis of patients with malignant tumor has been reported for a long time [ 13 , 23 , 24 , 33 – 35 ]. In CRC, low mRNA level of SQLE is associated with a better prognosis of patients [ 23 , 36 ].…”

“…Squalene is converted by SQLE to (S)-2,3-epoxysqualene during cholesterol synthesis, but limited information is currently available regarding the significance of (S)-2,3-epoxysqualene in cancer research [ 21 , 22 ]. SQLE is overexpressed in several cancers and the high expression of SQLE is closely related to the poor prognosis of cancer patients, including CRC [ 20 , 23 ]. It is reported that the poor survival of CRC patients with high SQLE expression is due to its promotion of tumor cell proliferation.…”

p53 and MYC-regulated squalene epoxidase as Achilles heel in colorectal cancer

“…The transcription factors p53 and MYC are both difficult to target therapeutically, but their dysregulation in cancer cells can generate new dependencies that provide treatment opportunities. In a recent study, the Hermeking group identified the squalene epoxidase (SQLE), a rate-limiting enzyme in the cholesterol biosynthesis, as a candidate target in colorectal cancer that harbors p53 mutation and elevated MYC activity 4 . It is the latest in a series of studies highlighting SQLE as a pharmaceutically exploitable target in colorectal cancer 5 - 7 .…”

“…By combining meta-analyses on p53 and MYC-dependent gene expression, Du et al . identified SQLE mRNA to be down-regulated by p53 and up-regulated by MYC 4 . Confirming earlier studies 5 , 6 , they found SQLE to be consistently higher expressed in colorectal cancer compared with normal tissue and to correlate with poor patient survival, and they corroborated that SQLE inhibition, such as through the SQLE inhibitor Terbinafine, decreased the viability of colorectal cancer cells.…”

“…Importantly, Du et al . discovered that the sensitivity of colorectal cancer cells to SQLE inhibition significantly correlated with the cells' p53 status and the dependency on MYC 4 .…”