FASN Gene Editing    

Fatty acid synthase (FASN) is a key enzyme in the de novo lipogenesis pathway, which catalyzes the synthesis of palmitate and coenzyme A (CoA) from malonyl-CoA and acetyl-CoA. Most normal human tissues preferentially use dietary lipids for synthesis of new structural lipids, and de novo fatty-acid synthesis is usually inhibited, with FASN expression maintained at low levels. In contrast, in cancer cells, the supply of cellular fatty acids is highly dependent on the de novo synthesis with the expression of many of these key enzymes being increased. FASN is highly expressed in many cancers, including prostate, ovarian, breast, glioblastoma, endometrial, thyroid, lung, colorectal, bladder, thyroid, oral, head and neck, hepatocellular, gastric carcinomas, melanoma, pancreatic, and soft tissue sarcomas. Thus, FASN has become an attractive therapeutic target for cancer drug discovery and development efforts.

FASN and Cancer

Upregulation of FASN is associated with the natural history of most human cancers, including breast carcinomas. FASN activation is an early and near universal marker of most human cancers and their precursor lesions, and is increased in a stage-dependent manner that is associated with worsened patient survival. The fact that there is a direct correlation between tumor stage and staining intensity, as well as metastatic ability shows that FASN not only provides a metabolic advantage for driving cancer cell survival and proliferation but also promotes a more aggressive tumor phenotype. In fact, tumor cell lines with high FASN expression show increased FA synthesis, which is inhibited by cerulenin, and such inhibition leads to growth delay that could only be rescued by supraphysiological concentrations of the FA palmitate in some models. Therefore, it comes as no surprise that studies analyzing the prognostic value of FASN overexpression confirm that its level of expression negatively correlates with prognosis. Similar to other molecular facets of deregulated cellular metabolism in tumor tissue, the lipogenic role of FASN in tumors has been perceived as an indirect, secondary phenomenon triggered by upstream signaling pathways (e.g. MAPK and PI3K-AKT-mTOR) commonly activated by different cancer-driven genetic lesions. The notion that FASN overexpression/hyperactivation is only required to support oncogene-directed anabolic proliferation and survival has been challenged by the recognition that FASN signaling can regulate not only cell proliferation, cell adhesion, cell survival, extracellular matrix (ECM) organization, migration, and invasion, but also the expression and activity of oncogenic proteins closely related to malignant transformation.

Figure 1. The metabolo-oncogenic nature of FASN in breast cancer. (Menendez J A, Lupu R., 2017)

FASN Inhibitors

Since the conception of the metabolo-oncogenic nature of FASN 10 years ago, FASN has received considerable attention as a therapeutic target. As early as 1972, the antifungal cerulenin was the first FASN inhibitor identified and it was widely evaluated as an anticancer agent in experimental models, showing activity against multiple tumor cell lines and xenograft models. In order to avoid the highly reactive nature of the cysteine-reactive epoxide in cerulein, Kuhahda et al. in 2000 reported the synthesis and antitumor activity of the synthetic, chemically stable inhibitor of FASN, C75, which was proven to inhibit purified mammalian FASN as a slow-binding inhibitor and also by blocking fatty acid synthesis in human cancer cells. Orlistat, a reduced form of the natural product lipstatin, was proposed as an antiobesity treatment in 1987 because of its potency and selectivity to inhibit pancreatic lipase. However, it was not until 1994 that Kridel et al. discovered that orlistat was an irreversible inhibitor of FASN through the thioesterase domain (TE) domain of the enzyme.

Although several different FASN inhibitors have been developed and comprehensively characterized in molecular and cell-based preclinical studies, most of the inhibitors described in the literature should be viewed as tool compounds rather than clinically valuable oncology drugs. With the discovery of next-generation FASN inhibitors with optimized pharmacological properties and in vivo tolerability, the pharmaceutical liabilities of first-generation FASN-targeting compounds are beginning to be circumvented. One of them, the first oral, selective, and potent reversible FASN inhibitor TVB-2640, has entered clinical trials.

FASN Gene Editing Services

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control FASN genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Service	Details	Alternative cell lines or animal species
FASN Gene Editing Cell Line Generation	gRNA design and synthesis Transfect the cell lines you're interested Select the high expression cells and sort monoclonal cell Validate the knockout/knockin/point mutation of FASN by PCR and sequencing Provide cryogenically preserved vials of stable cells and final reports	HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
FASN Gene Editing Animal Model Generation	FASN gene conventional knockout animals FASN gene conditional knockout animals FASN point mutation animals FASN knockin animals	Mouse, rat, rabbit, zebrafish, C. elegans, etc.

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