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

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 D 3 , 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.

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

“…However, this scientific area is quite poorly studied and further, we focus on the direct or indirect involvement of cholesterol precursors in cancers. We found that cholesterol precursors can be formally divided into three groups ( Table 4 ) depending on their impact on carcinogenesis [ 50 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 ].…”

DHCR24 Promotes Melanoma Stem-Like Cells Formation and Mediates Vemurafenib Resistance by Accumulating 27-Hydroxycholesterol

“…The intermediate metabolites of cholesterol have been demonstrated various functions in tumorigenesis. We and others previously showed that 7-dehydrocholesterol and vitamin K3 inhibited melanoma cell proliferation and induce apoptosis via AKT/MAPK signaling pathways [51][52][53]. while Nelson et al found that cholesterol metabolite 27-HC, as a partial agonist for the estrogen receptor and the liver X receptor, promoted tumor growth and metastasis in mouse models of mammary cancer [24].…”

Potential and functional prediction of six circular RNAs as diagnostic markers for colorectal cancer

“…For the cirReNET we built, there were many targeted genes involved in the mechanism of tumor genesis, such as AKT1 ( Liu et al, 2020 ), ErbB2 ( Li et al, 2018a ), ITGB7 ( Sun et al, 2020 ), BAX, MAPK, FBXL12 ( Nita et al, 2016 ), CCL7 ( Zhang et al, 2020b ) and so on. These genes also play very important roles in cell proliferation, apoptosis, movement, T-cell differentiation, adhesion, and polarity formation.…”