Kothapalli, K.S.D.; Park, H.G.; Kothapalli, N.S.L.; Brenna, J.T. FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer. Progress in Lipid Research 2023, 101242, doi:10.1016/j.plipres.2023.101242.
Kothapalli, K.S.D.; Park, H.G.; Kothapalli, N.S.L.; Brenna, J.T. FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer. Progress in Lipid Research 2023, 101242, doi:10.1016/j.plipres.2023.101242.
Kothapalli, K.S.D.; Park, H.G.; Kothapalli, N.S.L.; Brenna, J.T. FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer. Progress in Lipid Research 2023, 101242, doi:10.1016/j.plipres.2023.101242.
Kothapalli, K.S.D.; Park, H.G.; Kothapalli, N.S.L.; Brenna, J.T. FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer. Progress in Lipid Research 2023, 101242, doi:10.1016/j.plipres.2023.101242.
Abstract
The human chromosome 11q13 (HSA 11q13) genomic locus is a major cancer hotspot and has been established as the most frequently altered by amplification in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) localize to the 11q12- 13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of polyunsaturated and monounsaturated fatty acids, including unsaturated branched chain fatty acids (BCFA) by Δ6, Δ8, and Δ4 desaturation toward at least 16 substrates. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus in various cancer types. We searched PubMed and Google Scholar databases for articles that showed 11q13 amplification and studies reporting FADS2 function in various cancer types. FADS2 silencing causes synthesis of sciadonic acid (ScA, 5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to the eicosanoid precursor arachidonic acid (5Z,8Z,11Z,14Z–20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity leading to sapienic acid (16:1n10) biosynthesis from 16:0. Elevated serum mead acid (20:3n-9) levels were found in more than a third of hepatocellular carcinoma patients, indicative of an unsatisfied demand for arachidonic acid, likely as a substrate for eicosanoids. A highly expressed circular RNA (hsa_circ_022382) within an exonic region of FADS2 is associated with shorter overall survival in colorectal cancer patients. Similarly, in lung cancer tissues circFADS2 RNA is highly expressed. Palmitic acid (16:0) is a common substrate for SCD and FADS2. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders.
Medicine and Pharmacology, Oncology and Oncogenics
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