FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer

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.

High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates,MYCN-driven tumorigenesisin vivo

“…D-DHA is transported identically to the naturally occurring isotopologues of DHA and, thus, at steady state should reach similar concentrations in all body pools. HUFA production is generally suppressed in tumorigenesis by somatic changes as well as other mechanisms, [10] resulting at least in part in the reduction of the formation ROS and consequent downstream cell death. In the present studies, D-DHA was as effective as regular DHA in blocking tumor formation at similar doses.…”

“…[7][8][9] As we recently showed for neuroblastoma, transformation to malignancy alters fatty acid synthesis and levels within cells; fatty acid inputs are known to influence tumorigenesis. [10] In this study, we aimed to understand the effects of high-dose ω3 and ω6 HUFA DHA and EPA, and ARA, respectively. Prior reports on the effects of these HUFA suggest that all three can inhibit cancer cell growth, with a common mechanism of ROS reported.…”

Unsaturated fatty acid synthesis is associated with poor prognosis and differentially regulated byMYCNand tumor suppressor microRNAs in neuroblastoma

“…Together these studies suggest that Mead acid may provide a growth advantage in cancer, which could partially explain the elevated ω9 Mead acid production we see in NB cells. FADS2 dysregulation at the 11q13 major cancer hotspot region alters fatty acid metabolism in several cancer types [66]. FADS2 activity is promiscuous, it operates on at least 16 substrates catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation [23].…”

“…FADS2 dysregulation at the 11q13 major cancer hotspot region alters fatty acid metabolism in several cancer types (69). FADS2 operates on at least 16 substrates, catalyzing the biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation (24).…”

FADS2Indel polymorphism rs66698963 predicts colorectal polyp prevention by then-3 fatty acid EPA

“…The mechanism of the anti-neoplastic activity of EPA is uncertain, but the strongest evidence suggests that EPA antagonizes pro-tumorigenic signalling by competing with its n -6 HUFA homologue C20:4 n -6 arachidonic acid (AA) as a substrate for cyclooxygenase (COX)-dependent synthesis of pro-tumorigenic prostaglandin (PG) E 2 [4]. The rate-limiting step for endogenous AA synthesis from dietary C18:2 n -6 linoleic acid (LA) is Δ5-desaturation by fatty acid desaturase 1 (FADS1) [5-6]. We have previously characterized a functional 22 base pair (bp) insertion-deletion (Indel) polymorphism (rs66698963) in intron 1 of the neighbouring FADS2 gene, which is 137bp downstream of a sterol-response element [7].…”