The emerging role of 27-hydroxycholesterol in cancer development and progression: An update.

Oxysterols are cholesterol metabolites generated in the liver and other peripheral tissues as a mechanism of removing excess cholesterol. Oxysterols have a wide range of biological functions, including the regulation of sphingolipid metabolism, platelet aggregation, and apoptosis. However, it has been found that metabolites derived from cholesterol play essential functions in cancer development and immunological suppression. In this regard, research indicates that 27-hydroxycholesterol (27-HC) might act as an estrogen, promoting the growth of estrogen receptor (ER) positive breast cancer cells. The capacity of cholesterol to dynamically modulate signaling molecules inside the membrane and particular metabolites serving as signaling molecules are two possible contributory processes. 27-HC is a significant metabolite produced mainly through the CYP27A1 (Cytochrome P450 27A1) enzyme. 27-HC maintains cholesterol balance biologically by promoting cholesterol efflux via the liver X receptor (LXR) and suppressing de novo cholesterol production through the Insulin-induced Genes (INSIGs). It has been demonstrated that 27-HC is able to function as a selective ER regulator. Moreover, enhanced 27-HC production is in favor of the growth of end-stage malignancies in the brain, thyroid organs, and colon, as shown in breast cancer, probably due to pro-survival and pro-inflammatory signaling induced by unbalanced levels of oxysterols. However, the actual role of 27-HC in cancer promotion and progression remains debatable, and many studies are warranted to be performed to unravel the precise function of these molecules. This review article will summarize the latest evidence on the deleterious or beneficial functions of 27-HC in various types of cancer, such as breast cancer, prostate cancer, colon cancer, gastric cancer, ovarian cancer, endometrial cancer, lung cancer, melanoma, glioblastoma, thyroid cancer, adrenocortical cancer, and hepatocellular carcinoma.

Abdalkareem Jasim S ，Kzar HH ，Haider Hamad M ，Ahmad I ，Al-Gazally ME ，Ziyadullaev S ，Sivaraman R ，Abed Jawad M ，Thaeer Hammid A ，Oudaha KH ，Karampoor S ，Mirzaei R ... -  《-》

Hydroxylation site-specific and production-dependent effects of endogenous oxysterols on cholesterol homeostasis: Implications for SREBP-2 and LXR.

The cholesterol metabolites, oxysterols, play central roles in cholesterol feedback control. They modulate the activity of two master transcription factors that control cholesterol homeostatic responses, sterol regulatory element-binding protein-2 (SREBP-2) and liver X receptor (LXR). Although the role of exogenous oxysterols in regulating these transcription factors has been well established, whether endogenously synthesized oxysterols similarly control both SREBP-2 and LXR remains poorly explored. Here, we carefully validate the role of oxysterols enzymatically synthesized within cells in cholesterol homeostatic responses. We first show that SREBP-2 responds more sensitively to exogenous oxysterols than LXR in Chinese hamster ovary cells and rat primary hepatocytes. We then show that 25-hydroxycholesterol (25-HC), 27-hydroxycholesterol, and 24S-hydroxycholesterol endogenously synthesized by CH25H, CYP27A1, and CYP46A1, respectively, suppress SREBP-2 activity at different degrees by stabilizing Insig (insulin-induced gene) proteins, whereas 7α-hydroxycholesterol has little impact on SREBP-2. These results demonstrate the role of site-specific hydroxylation of endogenous oxysterols. In contrast, the expression of CH25H, CYP46A1, CYP27A1, or CYP7A1 fails to induce LXR target gene expression. We also show the 25-HC production-dependent suppression of SREBP-2 using a tetracycline-inducible CH25H expression system. To induce 25-HC production physiologically, murine macrophages are stimulated with a Toll-like receptor 4 ligand, and its effect on SREBP-2 and LXR is examined. The results also suggest that de novo synthesis of 25-HC preferentially regulates SREBP-2 activity. Finally, we quantitatively determine the specificity of the four cholesterol hydroxylases in living cells. Based on our current findings, we conclude that endogenous side-chain oxysterols primarily regulate the activity of SREBP-2, not LXR.

Saito H ，Tachiura W ，Nishimura M ，Shimizu M ，Sato R ，Yamauchi Y ... -  《-》

The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes.

Lappano R ，Recchia AG ，De Francesco EM ，Angelone T ，Cerra MC ，Picard D ，Maggiolini M ... -  《PLoS One》

Bird's eye view analysis of in situ cholesterol metabolic pathways in breast cancer patients and its clinicopathological significance in their subtypes.

Obesity has been known to increase the risks of breast cancer (BC) development and also to be associated with adverse clinical outcome of the patients. Abnormalities of cholesterol metabolism are not only related to obesity but also to biological or clinical behavior of BC patients. However, which metabolites or pathways of cholesterol metabolism could represent the characteristics of BC patients have remained virtually unknown. Therefore, in this study, we attempted to perform bird's eye view or comprehensive analysis of in situ or intra-tumoral cholesterol metabolic pathways using the multimodal approaches in order to elucidate the possible significance of cholesterol metabolites and its metabolic enzymes including CYP27A1, CYP7A1, and CYP46A1. GC-MS study using BC specimens was first performed in 60 BCE patients to evaluate cholesterol metabolism from cholesterol through oxysterols in both BC and normal tissues. Results of those analyses above lead to evaluating immunoreactivity and mRNA expression of CYP27A1, CYP7A1 and CYP46A1 in 213 and 153 BCE cases, respectively. Results of comprehensive GC-MS analysis did reveal that three oxysterols, 27-HC, 7α-HC and 24-HC were all related to malignant phenotypes in BC. 27-HC abundance was significantly associated with higher tumor stage (P = 0.0475) of BC patients. Luminal B type BC patients harboring high CYP27A1, the enzyme responsible for production of 27-HC were significantly associated with worse disease-free survival than those with low CYP27A1 (P = 0.0463). 7α-HC tended to be more abundant in HER2 positive and TNBC subtypes and higher levels of 7α-HC were also significantly associated with higher Ki-67 labeling index (P = 0.0022) and histological grade (P = 0.0286). CYP7A1, the enzyme involved in production of 7α-HC, was significantly more abundant in TNBC than other subtypes (vs Luminal A; P = 0.0321, vs Luminal B; P = 0.0048, vs HER2; P = 0.0103). The levels of 24-HC in BC were lower than normal breast tissues regardless of its subtypes. CYP46A1, the enzyme involved in the production of 24-HC, was detected only in 33 (15.5%) out of 213 BCE cases examined in this study. Results of our bird's eye view analysis of in situ or intra-tumoral cholesterol metabolism in BC patients did firstly reveal BC subtype dependent involvement of its different pathways. Results also indicated the therapeutic possibility of subtype dependent modification of cholesterol metabolizing pathways in BC patients.

Kosaka S ，Miyashita M ，McNamala K ，Nomura M ，Shima H ，Kawai M ，Sato I ，Harada-Shoji N ，Ishida T ，Choi MH ，Sasano H ... -  《-》

Our evolving understanding of how 27-hydroxycholesterol influences cancer.

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.

Ma L ，Cho W ，Nelson ER 《-》