SREBP1-dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait.

SREBP1-dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait.

Publication date: Jul 17, 2019

de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation of many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in cancers. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis, especially in melanomas. Elevated DNFA gene expression depends on the SREBP1 transcription factor in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, regulating their expression by recruiting RNA polymerase II to promoters for productive transcription elongation. We find that SREBP1-regulated DNFA represents a survival trait in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after the BRAF/MEK signaling pathway is blocked (e.g. by BRAF inhibitors), and DNFA expression remains higher in melanoma cells resistant to vemurafenib treatment than in untreated cells. Accordingly, DNFA pathway inhibition, whether by direct targeting of SREBP1 with antisense oligonucleotides, or through combinatorial effects of multiple DNFA enzyme inhibitors, exerts potent cytotoxic effects on both BRAFi-sensitive and -resistant melanoma cells. Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.

Open Access PDF

Wu, S. and N”a”ar, A.M. SREBP1-dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait. 23419. 2019 Sci Rep (9):1.

Concepts Keywords
Antisense Cancers
BRAF Indeed malignant melanoma
Combinatorial Elevated malignant melanoma
Cytotoxic Survival trait melanoma
Enzyme Survival proliferation metastasis
Fatty Acid Biosynthesis Branches of biology
Fatty Acid Synthesis Medicine
Malignant Melanoma Clinical medicine
MEK Melanoma
Melanoma Chloroarenes
Melanomas Cancer
Metastasis RTT
Mutation Vemurafenib
Oligonucleotides BRAF
Oncogenic Carcinogenesis
Polymerase Epigenetics and melanoma
Prognosis CDKN2A
Sci
Transcription
Transcription Factor
Transcription Regulation
Tumor
Vemurafenib

Semantics

Type Source Name
gene UNIPROT SIRT1
gene UNIPROT EP300
gene UNIPROT DUOXA1
gene UNIPROT TRIM9
disease MESH drug addiction
gene UNIPROT ZHX2
drug DRUGBANK Rasagiline
gene UNIPROT FGFR3
gene UNIPROT COL9A3
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT COL9A2
gene UNIPROT SCN8A
pathway BSID Oxidative Stress
disease MESH oxidative stress
gene UNIPROT MITF
pathway BSID Angiogenesis
disease MESH anaplastic thyroid carcinoma
pathway BSID mRNA Processing
drug DRUGBANK L-Lysine
gene UNIPROT TBATA
gene UNIPROT EHD1
disease MESH inflammation
gene UNIPROT TNF
gene UNIPROT TNMD
gene UNIPROT CYLD
drug DRUGBANK Tretamine
gene UNIPROT BRD2
gene UNIPROT ACTA1
pathway BSID Breast cancer
disease DOID breast cancer
disease MESH breast cancer
disease DOID adenocarcinoma
disease MESH adenocarcinoma
gene UNIPROT IDE
pathway BSID Colorectal cancer
disease DOID colorectal cancer
disease MESH colorectal cancer
gene UNIPROT GAD1
disease MESH Oncogene addiction
gene UNIPROT INTU
gene UNIPROT ARC
gene UNIPROT NOL3
drug DRUGBANK 3 7 11 15-Tetramethyl-Hexadecan-1-Ol
disease MESH ARC
gene UNIPROT SP1
gene UNIPROT DAND5
gene UNIPROT PSG1
gene UNIPROT ELAVL1
disease MESH heterozygotes
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
gene UNIPROT ADD1
gene UNIPROT C10orf90
gene UNIPROT SH2D2A
gene UNIPROT SCAP
drug DRUGBANK Cholesterol
pathway BSID Fatty acid metabolism
gene UNIPROT ALPK3
gene UNIPROT MAK
gene UNIPROT PRDM6
pathway BSID RNA polymerase
gene UNIPROT REST
gene UNIPROT CES2
gene UNIPROT CASP1
gene UNIPROT EMD
drug DRUGBANK Formaldehyde
gene UNIPROT POC1A
gene UNIPROT HOMER1
gene UNIPROT MARCKS
gene UNIPROT RIN2
gene UNIPROT BCL2L11
gene UNIPROT SMC3
gene UNIPROT GUCY2C
gene UNIPROT STAR
gene UNIPROT RRAD
gene UNIPROT TGM5
gene UNIPROT SDS
gene UNIPROT SBDS
drug DRUGBANK Sodium lauryl sulfate
gene UNIPROT PREP
gene UNIPROT PITRM1
gene UNIPROT NEB
drug DRUGBANK Folic Acid
gene UNIPROT BANK1
gene UNIPROT KIT
gene UNIPROT TRAV38-2DV8
gene UNIPROT TBXT
disease MESH G*C*A*A*G*A*C*A*G*C
disease MESH G*C*A*A*G*A*C*A*G*C
gene UNIPROT ELK3
gene UNIPROT EPHB1
gene UNIPROT SLC6A2
drug DRUGBANK Selenium
gene UNIPROT SNAP25
gene UNIPROT HERPUD1
drug DRUGBANK Streptomycin
drug DRUGBANK L-Glutamine
gene UNIPROT C2
gene UNIPROT ROS1
drug DRUGBANK Rosoxacin
disease MESH drug interaction
gene UNIPROT SPINK5
gene UNIPROT GNL3
gene UNIPROT KRAS
drug DRUGBANK Dimethyl sulfoxide
gene UNIPROT SYNM
gene UNIPROT FYN
gene UNIPROT PTPN5
drug DRUGBANK Serine
gene UNIPROT LITAF
disease MESH tumorigenesis
gene UNIPROT MENT
drug DRUGBANK Trestolone
gene UNIPROT ASCL1
gene UNIPROT EPHB2
gene UNIPROT MAPK1
drug DRUGBANK Dabrafenib
disease MESH death
gene UNIPROT PPARGC1A
gene UNIPROT TBPL1
gene UNIPROT LYVE1
gene UNIPROT RELA
disease MESH growth
gene UNIPROT MBTPS2
pathway BSID Fatty acids
pathway BSID Metabolism
gene UNIPROT FBXO8
gene UNIPROT DYRK3
gene UNIPROT IK
gene UNIPROT SOAT1
drug DRUGBANK L-Isoleucine
drug DRUGBANK L-Leucine
drug DRUGBANK Methionine
gene UNIPROT FUT1
disease MESH *****h
gene UNIPROT FBXO2
gene UNIPROT FBRS
drug DRUGBANK L-Phenylalanine
gene UNIPROT AKT1
gene UNIPROT PIK3CG
gene UNIPROT PIK3CB
gene UNIPROT PIK3CD
gene UNIPROT PIK3CA
gene UNIPROT ARHGAP9
disease DOID TSS
gene UNIPROT BCR
pathway BSID Chronic myeloid leukemia
disease DOID chronic myeloid leukemia
disease DOID lung cancer
disease MESH lung cancer
gene UNIPROT STUB1
pathway BSID TNF signaling
gene UNIPROT TLR4
gene UNIPROT SET
gene UNIPROT DEGS1
gene UNIPROT USP9X
gene UNIPROT SPIRE1
gene UNIPROT ESPL1
gene UNIPROT KRT17
gene UNIPROT PCSK2
gene UNIPROT KRT6B
gene UNIPROT CBX4
gene UNIPROT PKD2
gene UNIPROT CNTN3
gene UNIPROT OCA2
gene UNIPROT B3GALNT1
drug DRUGBANK Proline
disease MESH **P
gene UNIPROT NOVA2
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
drug DRUGBANK L-Aspartic Acid
disease MESH ACSL1********************************d
gene UNIPROT COL4A3BP
gene UNIPROT CREBBP
gene UNIPROT RAB8A
gene UNIPROT MED15
gene UNIPROT SREBF2
pathway BSID Translation
drug DRUGBANK Esomeprazole
gene UNIPROT NRAS
disease MESH risk factors
drug DRUGBANK Ademetionine
disease MESH melanocytic nevi
disease MESH separation
pathway BSID Fatty acid oxidation
gene UNIPROT ACSL1
gene UNIPROT KRT16
gene UNIPROT PCSK1
gene UNIPROT PKD1
gene UNIPROT FLVCR1
drug DRUGBANK Pidolic Acid
disease DOID PCA
gene UNIPROT HMGCR
gene UNIPROT HMGCS1
disease DOID cutaneous melanoma
gene UNIPROT THOP1
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT FBLN5
gene UNIPROT CEL
pathway BSID Release
gene UNIPROT SCD
gene UNIPROT CTSC
drug DRUGBANK Medrysone
gene UNIPROT CD36
gene UNIPROT FAT1
drug DRUGBANK Palmitic Acid
pathway BSID Adipogenesis
gene UNIPROT SCD5
gene UNIPROT FASN
gene UNIPROT ACACA
gene UNIPROT ACSS2
gene UNIPROT ACLY
gene UNIPROT ATP8A2
drug DRUGBANK ATP
gene UNIPROT AICDA
gene UNIPROT DECR1
drug DRUGBANK Coenzyme A
gene UNIPROT EAF2
disease DOID Cancer
drug DRUGBANK Coenzyme M
drug DRUGBANK Vemurafenib
gene UNIPROT MAP2K7
gene UNIPROT BRAF
pathway BSID Melanoma
disease MESH multiple
disease MESH metastasis
disease MESH cancers
pathway BSID Fatty acid biosynthesis
pathway BSID Fatty Acid Biosynthesis
disease DOID malignant melanoma
disease MESH malignant melanoma
pathway BSID Gene Expression
gene UNIPROT SREBF1

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