7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-κB signaling

Jia Liu; Feiliang Zhong; Lei Cao; Ruiying Zhu; Junze Qu; Lin Yang; Tingting Chen; Yunlong Hu; Ying Wang; Mingdong Yao; Wenhai Xiao; Chun Li; Bo Li; Yingjin Yuan

doi:10.3892/ol.2020.12261

7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-κB signaling

Oncol Lett. 2020 Dec;20(6):398. doi: 10.3892/ol.2020.12261. Epub 2020 Oct 29.

Authors

Jia Liu^{1

2}, Feiliang Zhong^{1

2}, Lei Cao^{1

2}, Ruiying Zhu^{1

2}, Junze Qu^{1

2}, Lin Yang³, Tingting Chen⁴, Yunlong Hu⁵, Ying Wang^{1

2}, Mingdong Yao^{1

2}, Wenhai Xiao^{1

2}, Chun Li^{1

2}, Bo Li^{1

2}, Yingjin Yuan^{1

2}

Affiliations

¹ Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, P.R. China.
² Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China.
³ Centre for Reproductive Medicine, Tianjin Medical University General Hospital, Tianjin 300041, P.R. China.
⁴ Department of Physiology, School of Basic Medical Sciences, Health Sciences Center, Shenzhen University, Shenzhen, Guangdong 518060, P.R. China.
⁵ Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Health Sciences Center, Shenzhen University, Shenzhen, Guangdong 518055, P.R. China.

Abstract

Melanoma is the most lethal cutaneous cancer with a high metastatic rate worldwide, causing ~55,500 deaths annually. Although the selective B-Raf oncogene serine/threonine-kinase (BRAF) inhibitors, dabrafenib and vemurafenib, have been approved for the treatment of BRAF-mutant metastatic melanoma, the 5-year survival rate remains unfavorable due to acquired therapy resistance. Therefore, it is of great importance to develop alternative therapeutic drugs and uncover their mechanisms for the treatment of melanoma. 7-dehydrocholesterol (7-DHC) has been demonstrated to inhibit melanoma, but the mechanism is unclear. Therefore, the present study aimed to elucidate the mechanisms of the inhibitory effect of 7-DHC in melanoma cells via analyzing the proliferation, migration, apoptosis, cell cycle and transcriptional sequencing of melanoma cells treated with 7-DHC, as well as constructing a gene signature according to public data of patients with melanoma. In the present study, 7-DHC, the precursor of vitamin D₃, was able to induce apoptosis and inhibit cell proliferation and invasion of melanoma cells in a dose-dependent manner. RNA sequencing of melanoma cells treated with different concentrations of 7-DHC revealed that, compared with untreated melanoma cells, 65 genes were downregulated, and genes involved in the regulation of NF-ĸB import into the nucleus and NF-ĸB signaling were significantly repressed. Consistently, the Akt kinase family was one of most common somatic mutation hotspots in patients with melanoma according to The Cancer Genome Atlas enrichment analysis. Furthermore, 7-DHC decreased the phosphorylation of Akt1-Ser473 rather than that of MEK1, and the decreased phosphorylation of Akt1 subsequently inhibited the translocation of free RELA proto-oncogene NF-κB subunit to the nucleus. Finally, by intersecting downregulated genes by 7-DHC treatment and upregulated genes in patients with melanoma, a 7-DHC gene signature was identified, which was negatively associated with the prognosis. Overall, the present results demonstrated that 7-DHC suppressed melanoma cell proliferation and invasion via the Akt1/NF-ĸB signaling pathway, and 7-DHC key target genes were negatively associated with the prognosis. These findings highlight the potential application of 7-DHC for the treatment of melanoma in the future.

Keywords: 7-dehydrocholesterol; Akt1/NF-ĸB; RNA sequencing; melanoma; prognosis.