The Role of Cholesterol in Cancer

Abstract

The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR.

Figure 1. Cancer patient survival and cholesterol synthesis pathway activity

A) Expression of a gene signature representing the activity of the cholesterol synthesis pathway was analyzed using the UCSC Cancer Genomic Browser. Statistically significant differences in survival of patients were observed between high (red) and low expressing (green) groups in melanoma, sarcoma, leukemia and glioma (right panel). In left panel, the expression heatmap of various cholesterol synthesis genes are shown for melanoma. The statistical track displayed under the heatmap shows the logarithmic plot of p-values for each genomic position and represents the statistical difference between the two subgroups (Student t-test with Bonferroni correction). A bar above the centerline indicates that the expression of a particular gene is higher in the red group compared to the green group; and a bar below the center line indicates that the expression of the particular gene is higher in the green group compared to the red group. The data is available through the UCSC Cancer Brower (goo.gl/56UxKy). HR: Hazard ratio (Mantel-Haenszel) of red vs green group (95% Confidence Interval); p=p value of Mantel-Cox log-rank test; MS: Median-survival; n= number of patients. B) Oncogenic signals initiated from RTK/AKT/mTOR (1), RTK/RAS (2) or mutated p53 (3) induce the activity of SREBP transcription factor, the major regulator of genes encoding cholesterol synthesis as well as import proteins (4). Intracellular cholesterol is transported to the mitochondria by START domain family of proteins (5). Accumulation of cholesterol in mitochondria can suppress apoptosis by inhibiting release of apoptotic proteins from mitochondria (6). However, in mitochondria cholesterol is also metabolized to 27-hydroxycholesterol 27-HC), which induces tumor growth in certain cancers (7). Under steady state conditions, excess intracellular cholesterol is exported out by ABC-transporter family proteins, mainly by ABCA1 (8). Oncogenic signals may inhibit ABCA1 expression by inducing miR-33 leading to intracellular cholesterol accumulation (9). C) Breast cancer patients with mutated p53 showed increased expression of various cholesterol synthesis genes; Error bars show standard deviation. *** Student t-test p < 0.001.

Figure 2. Genetic alterations in cholesterol homeostasis genes in the melanoma patient cohort of the TCGA database

A) Survival of cancer patients based on the STAR+STARD3 gene signature (goo.gl/6zT8kM); B) Around sixty percent of the tumors from 278 melanoma patients in the TCGA cohort, displayed increased gene copy number or expression of cholesterol synthesis genes (goo.gl/tqbV4h); C) Copy number increases of cholesterol homeostasis genes can be linked to amplification sites of known oncogenes, such as AKT3, NOTCH2, MYC or EP300 or deleted with along with genes linked to cancer. SC5D is an example of a gene co-deleted together with several cholesterol export related genes. HR: Hazard ratio (Mantel-Haenszel) of red vs green group (95% Confidence Interval); p=p value of Mantel-Cox log-rank test; MS: Median-survival; n= number of patients.