Abstract 3085: Cholesterol sulfotransferase SULT2B1b suppresses prostate tumor growth and regulates cholesterol metabolism in prostate cancer cells
Authors: Jiang Yang, Dilinaer Wusiman, Timothy L. Ratliff
Journal: Cancer Research (2024)

Abstract Prostate cancer (PrCa) ranks as the second leading cause of cancer death in males in the United States. The 5-year survival rate drops drastically from 100% in patients with early-stage confined PrCa to 30% in those with advanced metastatic PrCa. Patients with advanced PrCa face limited long-term treatment options, often developing resistance to androgen-deprivation therapy and chemotherapy. Identifying and targeting pivotal molecules or pathways in advanced PrCa can substantially enhance patient survival. Our previous findings unveiled an inverse relationship between cholesterol sulfotransferase SULT2B1b and the severity of human PrCa. The highest levels of SULT2B1b were observed in the epithelium of normal prostates, with a progressive decrease as cancer advanced. The lowest levels were found in the most advanced metastatic samples. This study aims to determine whether SULT2B1b performs any active and critical functions in PrCa progression and assess whether it regulates cholesterol metabolism in PrCa cells. We generated SULT2B1b knockout (KO) clones from mouse PrCa cell line MyC-CaP and established inducible SULT2B1b overexpression lines from androgen receptor (AR)+ LNCaP and AR- PC3 human PrCa cells. These modified mouse and human cells were implanted into syngeneic FVB mice and immunodeficient NRG mice, respectively. MyC-CaP KO cells formed significantly larger tumors compared to parental cells, accompanied by reduced survival rates. In contrast, both LNCaP and PC3 tumors with induced SULT2B1b exhibited smaller sizes compared to control tumors, leading to improved survival rates. To investigate the impact of SULT2B1b on cholesterol metabolism and the underlying mechanisms behind SULT2B1b-regulated tumor growth, we examined genes related to lipoprotein signaling and cholesterol metabolism in MyC-CaP SULT2B1b KO cells using PCR arrays and qRT-PCR. Genes responsible for cholesterol uptake and synthesis (e.g. Ldlr, Cyp51, Sorl1, Pcsk9 and Insig1) were among the top upregulated genes, while genes controlling cholesterol efflux (e.g. Abca1) and esterification (e.g. Soat1 and Soat2) were downregulated in KO cells. Consistent with these gene expression patterns, intracellular cholesterol levels significantly increased in KO cells. Interestingly, although SULT2B1b did not affect cell proliferation under normal conditions, KO cells exhibited faster growth than parental cells when cultured in lipid-depleted or charcoal-stripped media, possibly due to altered intracellular cholesterol levels. In summary, these findings align with the expression pattern of SULT2B1b in human PrCa, demonstrating that SULT2B1b inhibits tumor growth, whereas its removal promotes tumor growth. This suggests SULT2B1b may serve as a critical tumor suppressor in PrCa. Its modulation of tumor growth may occur through the regulation of cholesterol metabolism. Citation Format: Jiang Yang, Dilinaer Wusiman, Timothy L. Ratliff. Cholesterol sulfotransferase SULT2B1b suppresses prostate tumor growth and regulates cholesterol metabolism in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3085.