Our evolving understanding of how 27-hydroxycholesterol influences cancer

Abstract

Cholesterol has been implicated in the pathophysiology and progression of several cancers now, although the mechanisms by which it influences cancer biology are just emerging. Two likely contributing mechanisms are the ability for cholesterol to directly regulate signaling molecules within the membrane, and certain metabolites acting as signaling molecules. One such metabolite is the oxysterol 27-hydroxycholesterol (27HC), which is a primary metabolite of cholesterol synthesized by the enzyme Cytochrome P450 27A1 (CYP27A1). Physiologically, 27HC is involved in the regulation of cholesterol homeostasis and contributes to cholesterol efflux through liver X receptor (LXR) and inhibition of de novo cholesterol synthesis through the insulin-induced proteins (INSIGs). 27HC is also a selective modulator of the estrogen receptors. An increasing number of studies have identified its importance in cancer progression of various origins, especially in breast cancer. In this review, we discuss the physiological roles of 27HC targeting these two nuclear receptors and the subsequent contribution to cancer progression. We describe how 27HC promotes tumor growth directly through cancer-intrinsic factors, and indirectly through its immunomodulatory roles which lead to decreased immune surveillance and increased tumor invasion. This review underscores the importance of the cholesterol metabolic pathway in cancer progression and the potential therapeutic utility of targeting this metabolic pathway.

Figure 1.. Cholesterol-27HC axis promotes tumor progression.

The enzyme CYP27A1 catalyzes the conversion of cholesterol to 27HC. 27HC is a ligand for both the ERs and LXRs. Through the ERs expressed in certain cancers (ERα for breast, ERβ or prostate; see text for details), 27HC promotes proliferation in a cancer cell-intrinsic manner. The activation of LXR in cancer cells leads to an upregulation of chemotherapy efflux pump Pgp and support chemoresistance of those cells, but has also been shown to induce cholesterol efflux and slow proliferation. In a cancer cell-extrinsic manner, 27HC works on LXRs in antigen (Ag)-presenting macrophages and other myeloid immune cells such as neutrophils to suppress T cell activity, which ultimately suppresses immune surveillance and drives cancer progression. Figure created with BioRender (BioRender.com).

Figure 2.. The LXRs have multifaceted contributions to cancer progression.

When the LXRs were activated by certain synthetic agonists, MDSC population was depleted, leading to augmented T cell activity and cancer death in various cancer models. On the other hand, 27HC has been shown to increase the recruitment and differentiation of other types of myeloid cells including MDSCs to the tumor site, resulting in impaired T cell function. The precise role of LXR in this process has not been determined. 27HC could activate LXR in Ag-presenting macrophages and other myeloid cells such as neutrophils, resulting in a phenotype that confers suppressive effects on T cells. Additionally, endogenously produced oxysterols have been shown to decrease the expression of CCR7 within dendritic cells, impairing their ability to migrate towards tumor sites. Figure created with BioRender.