The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis

Abstract

FABPs (fatty-acid-binding proteins) are a family of low-molecular-mass intracellular lipid-binding proteins consisting of ten isoforms. FABPs are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting these ligands to the appropriate compartments in the cell. FABP5 is overexpressed in multiple types of tumours. Furthermore, up-regulation of FABP5 is strongly associated with poor survival in triple-negative breast cancer. However, the mechanisms underlying the specific up-regulation of the FABP5 gene in these cancers remain poorly characterized. In the present study, we determined that FABP5 has a typical CpG island around its promoter region. The DNA methylation status of the CpG island in the FABP5 promoter of benign prostate cells (PNT2), prostate cancer cells (PC-3, DU-145, 22Rv1 and LNCaP) and human normal or tumour tissue was assessed by bisulfite sequencing analysis, and then confirmed by COBRA (combined bisulfite restriction analysis) and qAMP (quantitative analysis of DNA methylation using real-time PCR). These results demonstrated that overexpression of FABP5 in prostate cancer cells can be attributed to hypomethylation of the CpG island in its promoter region, along with up-regulation of the direct trans-acting factors Sp1 (specificity protein 1) and c-Myc. Together, these mechanisms result in the transcriptional activation of FABP5 expression during human prostate carcinogenesis. Importantly, silencing of Sp1, c-Myc or FABP5 expression led to a significant decrease in cell proliferation, indicating that up-regulation of FABP5 expression by Sp1 and c-Myc is critical for the proliferation of prostate cancer cells.

Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth

“…We first determined whether our second‐generation FABP5 inhibitors produce cytotoxicity in PCa cells. The cytotoxic effects of SBFI‐102 (Figure A) and SBFI‐103 (Figure B) were assessed in human‐derived PC3, DU‐145, and 22Rv1 cells that express FABP5 . SBFI‐102 and SBFI‐103 produced dose‐dependent cytotoxicity in each cell‐line tested: PC3 cells with IC 50 values of 11.4 and 6.3 µM, respectively; DU‐145 cells with half‐maximal inhibitory concentration (IC 50 ) values of 8.9 and 3.3 µM, respectively; and 22Rv1 cells with IC 50 values of 10.1 and 3.1 µM, respectively.…”

“…We employed subcutaneous tumor growth assays to determine whether the interactions between SBFI‐102/SBFI‐103 and docetaxel extend to the in vivo setting. Docetaxel was chosen as it is the standard of care first‐line treatment for chemotherapy naïve castration‐resistant PCa, and PC3 cells were chosen due to their heightened tumorigenicity and expression of FABP5 relative to DU‐145 and 22Rv1 cells . BALB/c nude mice were implanted with PC3 cells and inhibitor treatments were initiated when tumors reached a volume of approximately 150 to 200 mm 3 .…”

“…The normal prostate lacks FABP5 expression but it becomes highly upregulated in PCa and the degree of its upregulation correlates with increasing Gleason scores, indicating that advanced metastatic prostate tumors express the highest levels of FABP5 . Mirroring this expression pattern, PCa cell‐lines with low metastatic potential lack FABP5 expression, whereas PCa cell‐lines with high metastatic potential demonstrate elevated FABP5 expression levels . Introduction of FABP5 to PCa cell‐lines with low metastatic potential enhances cell migration, invasion, and tumor formation, while its inhibition in PCa cell‐lines with high metastatic potential attenuates these features .…”

“…5,8,12,13 Mirroring this expression pattern, PCa cell-lines with low metastatic potential lack FABP5 expression, whereas PCa cell-lines with high metastatic potential demonstrate elevated FABP5 expression levels. 5,14 Introduction of FABP5 to PCa cell-lines with low metastatic potential enhances cell migration, invasion, and tumor formation, while its inhibition in PCa celllines with high metastatic potential attenuates these features. 7,9,14 This positions FABP5 as a potential therapeutic target to treat PCa.…”

“…5,14 Introduction of FABP5 to PCa cell-lines with low metastatic potential enhances cell migration, invasion, and tumor formation, while its inhibition in PCa celllines with high metastatic potential attenuates these features. 7,9,14 This positions FABP5 as a potential therapeutic target to treat PCa.…”