Lipid desaturation-associated endoplasmic reticulum stress regulates MYCN gene expression in hepatocellular carcinoma cells.

Szczegóły
Abstrakt

Tytuł:: Lipid desaturation-associated endoplasmic reticulum stress regulates MYCN gene expression in hepatocellular carcinoma cells.
Autorzy:: Qin XY; Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan. .
Su T; Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan.; Department of Intensive Care Unit, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, China.
Yu W; Department of Intensive Care Unit, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, China.
Kojima S; Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan.
Źródło:: Cell death & disease [Cell Death Dis] 2020 Jan 27; Vol. 11 (1), pp. 66. Date of Electronic Publication: 2020 Jan 27.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: London : Nature Pub. Group
MeSH Terms:: Carcinoma, Hepatocellular/*metabolism
Endoplasmic Reticulum Stress/*genetics
Fatty Acids, Unsaturated/*metabolism
Liver Neoplasms/*metabolism
N-Myc Proto-Oncogene Protein/*metabolism
Activating Transcription Factor 3/genetics ; Activating Transcription Factor 3/metabolism ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Chromatography, Liquid ; Endoplasmic Reticulum Stress/drug effects ; Fatty Acids, Unsaturated/chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Liver Neoplasms/genetics ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Metabolome ; N-Myc Proto-Oncogene Protein/genetics ; Neoplastic Stem Cells/metabolism ; Organoids/drug effects ; Organoids/metabolism ; RNA, Small Interfering ; RNA-Seq ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Stearoyl-CoA Desaturase/antagonists & inhibitors ; Tretinoin/analogs & derivatives ; Tretinoin/metabolism ; Tretinoin/pharmacology
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Substance Nomenclature:: 0 (ATF3 protein, human)
0 (Activating Transcription Factor 3)
0 (Fatty Acids, Unsaturated)
0 (MYCN protein, human)
0 (N-Myc Proto-Oncogene Protein)
0 (RNA, Small Interfering)
5688UTC01R (Tretinoin)
81485-25-8 (3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid)
EC 1.14.19.1 (SCD1 protein, human)
EC 1.14.19.1 (Stearoyl-CoA Desaturase)
Entry Date(s):: Date Created: 20200129 Date Completed: 20201001 Latest Revision: 20210126
Update Code:: 20240105
PubMed Central ID:: PMC6985230
DOI:: 10.1038/s41419-020-2257-y
PMID:: 31988297
: Czasopismo naukowe

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide due to its high rate of recurrence, in part because of cancer stem cell (CSC)-dependent "field cancerization". Recently, we identified that the oncogene v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) marked CSC-like subpopulations in heterogeneous HCC and served as a therapeutic target and prognostic marker for HCC. In this study, we explored the molecular basis of upregulated MYCN gene expression in HCC cells. Liquid chromatograph time-of-flight mass spectrometry-based metabolome analysis demonstrated that the content of unsaturated fatty acids was increased in MYCN high expression (MYCN high ) CSC-like HCC cells. Inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against stearoyl-CoA desaturase-1 (SCD1) suppressed cell proliferation as well as MYCN gene expression in MYCN high HCC cells, grown as both monolayer and spheres. Further mechanistic study using RNA-seq based transcriptome analysis revealed that endoplasmic reticulum (ER) stress related signaling networks such as endocannabinoid cancer inhibition pathway were under the control of SCD1 in MYCN high HCC cells. Furthermore, the expression of ER stress-inducible transcription suppressor cyclic AMP-dependent transcription factor (ATF3) was downregulated in MYCN high CSC-like HCC cells and CSC-rich spheroids, which was upregulated by inhibition of lipid desaturation or treatment with acyclic retinoid (ACR). Lipid profiling using NMR spectroscopy revealed that the ACR dramatically reduced the content of unsaturated fatty acids in HCC cells. The chemical inducer of ER stress inhibited MYCN gene expression, while the chemical inhibitor of ER stress or knockdown of ATF3 gene expression partially rescued the suppression of MYCN gene expression by ACR in MYCN high HCC cells. These data suggested that lipid desaturation-mediated ER stress signaling regulates MYCN gene expression in HCC cells and serves as a promising therapeutic target for the treatment and prevention of HCC.

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