Knockdown of lecithin retinol acyltransferase increases all‐trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells

Abstract

Retinoids such as all-trans retinoic acid (ATRA) influence cell growth, differentiation and apoptosis and may play decisive roles in tumor development and progression. An essential retinoid-metabolizing enzyme known as lecithin retinol acyltransferase (LRAT) is expressed in melanoma cells but not in melanocytes catalysing the esterification of all-trans retinol (ATRol). In this study, we show that a stable LRAT knockdown (KD) in the human melanoma cell line SkMel23 leads to significantly increased levels of the substrate ATRol and biologically active ATRA. LRAT KD restored cellular sensitivity to retinoids analysed in cell culture assays and melanoma 3D skin models. Furthermore, ATRA-induced gene regulatory mechanisms drive depletion of added ATRol in LRAT KD cells. PCR analysis revealed a significant upregulation of retinoid-regulated genes such as CYP26A1 and STRA6 in LRAT KD cells, suggesting their possible involvement in mediating retinoid resistance in melanoma cells. In conclusion, LRAT seems to be important for melanoma progression. We propose that reduction in ATRol levels in melanoma cells by LRAT leads to a disturbance in cellular retinoid level. Balanced LRAT expression and activity may provide protection against melanoma development and progression. Pharmacological inhibition of LRAT activity could be a promising strategy for overcoming retinoid insensitivity in human melanoma cells.

A Novel Signature of 23 Immunity-Related Gene Pairs Is Prognostic of Cutaneous Melanoma

“…Information on every GO term is provided in Table S1. As shown in Figure S6, several melanoma progression-related pathways, including oxidative phosphorylation (28,29), retinol metabolism (30)(31)(32), and ribosome (33,34), were significantly upregulated in the highrisk group (padj < 0.05). Collectively, the results obtained using the IRGP signature provide evidence of the molecular mechanisms affected by CM and, thus, the predictive power of this signature for the prognosis of CM patients.…”

All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway

“…Therefore, the restoration of the osteogenic ability of BMP9 in OS cells may contribute to the treatment of OS. ATRA promotes terminal differentiation of immature cells, including various types of cancer cells (25)(26)(27)(28)(29)(30), and can promote osteogenic differentiation (29)(30)(31)(32)(33)48). Yang et al reported that ATRA could inhibit proliferation, induce apotosis and promote osteogenic differentiation in 143B cells, but the effect of apotosis induced by ATRA is not obvious.…”

“…The biological effects of ATRA are mediated by two families of nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), which work as RAR/RXR heterodimers and bind to retinoic acid response elements in the promoter regions of retinoid-responsive genes (24). ATRA can induce differentiation in acute promyelocytic leukaemia (APL) and other tumour types, such as neuroblastoma, breast cancer and melanoma (25)(26)(27)(28). Additionally, ATRA can induce osteoblastic differentiation of osteosarcoma cells both in vivo and in vitro (29,30).…”

A Novel Signature of 23 Immunity-Related Gene Pairs is Prognostic of Cutaneous Melanoma

“…Information of every GO term is shown in Table S1. As shown in Figure S4, multiple melanoma progression-related pathways, including oxidative phosphorylation [24,25], retinol metabolism [26][27][28], and ribosome [29,30], were signi cantly upregulated in the high risk group (padj < 0.05). Collectively, these results provided evidence of molecular mechanisms affected by the IRGP signature and, thus, predictive of the prognosis of CM patients.…”