Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1‐mediated MAPK signaling

Abstract

Background Colorectal cancer (CRC) is one of the most malignant tumors with high incidence, yet its molecular mechanism is not fully understood, hindering the development of targeted therapy. Metabolic abnormalities are a hallmark of cancer. Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy. In this study, we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms. Methods We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC. Squalene epoxidase (SQLE) was identified to be highly upregulated in CRC patients. The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability, colony and organoid formation, intracellular cholesterol concentration and xenograft tumor growth. The molecular mechanism of SQLE function was explored by combining transcriptome and untargeted metabolomics analysis. Western blotting and real‐time PCR were used to assess MAPK signaling activation by SQLE. Results SQLE‐related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis. SQLE promoted CRC growth in vitro and in vivo. Inhibition of SQLE reduced the levels of calcitriol (active form of vitamin D3) and CYP24A1, followed by an increase in intracellular Ca2+ concentration. Subsequently, MAPK signaling was suppressed, resulting in the inhibition of CRC cell growth. Consistently, terbinafine, an SQLE inhibitor, suppressed CRC cell proliferation and organoid and xenograft tumor growth. Conclusions Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1‐mediated MAPK signaling, highlighting SQLE as a potential therapeutic target for CRC treatment.

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

“…Moreover, a positive correlation between intestinal intact breaking bacteria E.Coli and A.Muciniphila and cholesterol in MNCs further indicating that up-regulation of cholesterol is associated with intestinal break. As we all know, SQLE is a key enzyme in cholesterol biosynthesis, which has been reported to be oncogenic in several disease [25,26]. Our study fulfills a further recognition of SQLE in AML.…”

Squalene synthase predicts poor prognosis in stage I‐III colon adenocarcinoma and synergizes squalene epoxidase to promote tumor progression

“…In our previous study, we found that SQLE promoted colon cancer cell proliferation in vitro and in vivo 25 . Squalene synthase functions upstream of SQLE in the steroid synthesis pathway.…”

“…In our previous study, we found that SQLE promoted colon cancer cell proliferation in vitro and in vivo. 25 Squalene synthase functions upstream of SQLE in the steroid synthesis pathway. Accordingly, we generated the FDFT1/SQLE double-KD HT29 cell line to explore the possibility of the combined functions of FDFT1 and SQLE on colon cancer cell proliferation.…”

Modeling Reactive Species Metabolism in Colorectal Cancer for Identifying Metabolic Targets and Devising Therapeutics

“…Higher expression of LPCAT1 in CRC patients is associated with worse prognosis [48]. Among the genes and gene combinations mentioned in the Table 8, knock down effects of only the first two, PTGS2 and SQLE have been studied in CRC cell lines and animal models [41, 47]. The other proposed targets are found to have an effect on CRC cell line based on the negative log fold values from DEMETER database but are yet to be studied as gene targets in different CRC cell lines.…”

“…The other proposed targets are found to have an effect on CRC cell line based on the negative log fold values from DEMETER database but are yet to be studied as gene targets in different CRC cell lines. PTGS2 is over-expression is correlated with a lower survival rate among CRC patients [41] Squalene monoxygenase (cholesterol synthesis) SQLE stimulates CRC cell proliferation by regulating the cell cycle and its overexpression is associated with poor prognosis in CRC patients in the primary stages [47] 1-Acylglycerol-3-phosphate O-acyltransferase (fatty acid metabolism) LPCAT1 stimulates CRC development by enhancing membrane biosynthesis and its a risky prognostic gene in CRC patients [48,49] Linoleoyl-CoA desaturase (fatty acid synthesis) Upregulation of FADS2 promotes colon cancer proliferation and tumor growth and yet to be explored as CRC target [43] Carbonyl reductase (xenobiotics metabolism and antioxidant defense)…”