Cholesterol epoxide hydrolase and cancer

Cholesterol epoxide hydrolase (ChEH) catalyzes the hydration of cholesterol-5,6-epoxides (5,6-EC) into cholestane-3β,5α,6β-triol. ChEH is a hetero-oligomeric complex called the anti-estrogen binding site (AEBS) comprising 3β-hydroxysterol-Δ8-Δ7-isomerase (D8D7I) and 3β-hydroxysterol-Δ7-reductase (DHCR7). D8D7I and DHCR7 regulate cholesterol biosynthesis, fetal development and growth, tumor cell differentiation and death. The un-reactivity of 5,6-EC toward nucleophiles has recently been demonstrated indicating that 5,6-EC are not alkylating and carcinogenic agents as first postulated. Here we discuss recent advances in the molecular characterization of ChEH, its potential role in cancer progression and resistance as well as the interest of inhibiting ChEH and to accumulate 5,6-EC which may contribute to the anti-tumor and chemopreventive action of ChEH inhibitors used in the clinic such as tamoxifen.

Graphical abstractDownload high-res image (140KB)Download full-size imageHighlights► ChEH is selective for 5,6α-EC and 5,6β-EC substrates. ► 5,6α-EC and 5,6β-EC are un-reactive toward nucleophiles and are not alkylating agents. ► ChEH is a target for anti-cancer agents used in the clinic such as tamoxifen. ► ChEH is a complex, also called AEBS, comprising the D8D7I and DHCR7 enzymes.