Research Paper Volume 12, Issue 14 pp 15021—15036
NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling
- 1 Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, China
- 2 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
- 3 Guangdong Key Laboratory for Genome Stability and Disease Prevention, Carson International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen 518060, China
- 4 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University, Health Science Center, Shenzhen 518055, China
Received: April 3, 2020 Accepted: June 5, 2020 Published: July 25, 2020https://doi.org/10.18632/aging.103562
How to Cite
Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Aberrant activation of the cholesterol biosynthesis supports tumor cell growth. In recent years, significant progress has been made by targeting rate-limiting enzymes in cholesterol biosynthesis pathways to prevent carcinogenesis. However, precise mechanisms behind cholesterol degradation in cancer cells have not been comprehensively investigated. Here, we report that codon optimization of the orthologous cholesterol 7-desaturase, NVD-BM from Bombyx mori, significantly slowed melanoma cell proliferation and migration, and inhibited cancer cell engraftment in nude mice, by converting cholesterol to toxic 7-dehydrocholesterol. Based on these observations, we established a synthetic genetic circuit to induce melanoma cell regression by sensing tumor specific signals in melanoma cells. The dual-input signals, RELA proto-oncogene (RELA) and signal transducer and activator of transcription 1 (STAT1), activated NVD-BM expression and repressed melanoma cell proliferation and migration. Mechanically, we observed that NVD-BM decreased Akt1-ser473 phosphorylation and inhibited cytoplasmic RELA translocation. Taken together, NVD-BM was identified as a tumor suppressor in malignant melanoma, and we established a dual-input biosensor to promote cancer cell regression, via Akt1/NF-κB signaling. Our results demonstrate the potential therapeutic effects of cholesterol 7-desaturase in melanoma metabolism, and provides insights for genetic circuits targeting 7-dehydrocholesterol accumulation in tumors.
7-DHC: 7-dehydrocholesterol; RTCA: real-time cellular analysis; NC: negative control; HE: hematoxylin-eosin; GC-MS: gas chromatography-mass spectrometry; qRT-PCR: real time quantitative PCR; GSEA: gene-set enrichment analysis; GEO: gene expression omnibus; TCGA: the cancer genome atlas; GTEX: the genotype-tissue expression.