A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Agrawal, Praveen; Fontanals-Cirera, Bárbara; Sokolova, Elena; Jacob, Samson T.; Vaiana, Christopher A.; Argibay, Diana; Dávalos, Verónica; McDermott, Meagan; Nayak, Shruti; Darvishian, Farbod; Castillo, Maurício; Ueberheide, Beatrix; Osman, Iman; Fenyö, David; Mahal, Lara K.; Hernando, Eva

doi:10.1016/j.ccell.2017.05.007

Cited by 262 publications

(285 citation statements)

References 66 publications

Supporting

Mentioning

277

Contrasting

Unclassified

Order By: Relevance

“…We next performed motif analysis on the top 150 SEs (Figure 5B) and identified JUN and FOSL1/2 (of the AP-1 TF complex), TEAD1/4, and TGIF1/2 (Figure 5H), all of which have been implicated in melanoma or other cancers (Agrawal et al, 2017; Ozanne et al, 2007; Verfaillie et al, 2015; Xiang et al, 2015). ChIP-seq analysis showed FOSL2 and TEAD4 enrichment at melanoma SEs and TEs (Figures 5I and S6C).…”

Section: Resultsmentioning

confidence: 99%

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

et al. 2017

Self Cite

View full text Add to dashboard Cite

SUMMARY Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a trans-membrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.

show abstract

Section: Resultsmentioning

confidence: 99%

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several glycans on the tumor surface, such as Tn, sialyl-Tn, and T antigen, have been identified as being mediators of critical pathophysiologic events during the various steps of tumor progression, such as cell-cycle dysregulation, cell adhesion, invasion activity, and angiogenesis (9,10). For example, upregulation of fucosylation by fucosyltransferase 8 in melanoma drives invasion and metastasis (11). Tumor-associated carbohydrates have been linked to drug resistance in multiple in vitro models (12) and also indicated as prognostic markers by which to predict therapeutic efficacy in patients with breast cancer who have been treated with anthracycline-containing adjuvant chemotherapy (13).…”

mentioning

confidence: 99%

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

et al. 2018

View full text Add to dashboard Cite

Disseminated castration-resistant prostate cancer (CRPC) is a common disease in men that is characterized by limited survival and resistance to androgen-deprivation therapy. The increase in human epidermal growth factor receptor 2 (HER2) signaling contributes to androgen receptor activity in a subset of patients with CRPC; however, enigmatically, HER2-targeted therapies have demonstrated a lack of efficacy in patients with CRPC. Aberrant glycosylation is a hallmark of cancer and involves key processes that support cancer progression. Using transcriptomic analysis of prostate cancer data sets, histopathologic examination of clinical specimens, and in vivo experiments of xenograft models, we reveal in this study a coordinated increase in glycan-binding protein, galectin-4, specific glycosyltransferases of core 1 synthase, glycoprotein- N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) and ST3 beta-galactoside α-2,3-sialyltransferase 1 (ST3GAL1), and resulting mucin-type O-glycans during the progression of CRPC. Furthermore, galectin-4 engaged with C1GALT1-dependent O-glycans to promote castration resistance and metastasis by activating receptor tyrosine kinase signaling and cancer cell stemness properties mediated by SRY-box 9 (SOX9). This galectin-glycan interaction up-regulated the MYC-dependent expression of C1GALT1 and ST3GAL1, which altered cellular mucin-type O-glycosylation to allow for galectin-4 binding. In clinical prostate cancer, high-level expression of C1GALT1 and galectin-4 together predict poor overall survival compared with low-level expression of C1GALT1 and galectin-4. In summary, MYC regulates abnormal O-glycosylation, thus priming cells for binding to galectin-4 and downstream signaling, which promotes castration resistance and metastasis.-Tzeng, S.-F., Tsai, C.-H., Chao, T.-K., Chou, Y.-C., Yang, Y.-C., Tsai, M.-H., Cha, T.-L., Hsiao, P.-W. O-Glycosylation-mediated signaling circuit drives metastatic castration-resistant prostate cancer.

show abstract

“…Similar mechanisms have also been shown to regulate transcription of glycogenes producing tumor‐related glycans likely supporting malignant transformation . In addition to epigenetic‐based mechanisms, classical signaling‐mediated transcription factor activation has also been shown to regulate the transcription of glycogenes . For example, endoplasmic reticulum (ER) stress‐induced activation of XBP1 promotes expression of mannosidase and N ‐acetylglucosamine (GlcNAc) transferases (MGAT1, MAN1A1, and MGAT2) involved in N‐glycan maturation, thus shifting the glycosylation profile of secreted cargoes from oligomannose toward mature, hybrid, and complex type N‐glycans .…”

Section: Factors Affecting Glycan Outputmentioning

confidence: 99%

Translation of genome to glycome: role of the Golgi apparatus

et al. 2019

View full text Add to dashboard Cite

Glycans are one of the four biopolymers of the cell and they play important roles in cellular and organismal physiology. They consist of both linear and branched structures and are synthesized in a nontemplated manner in the secretory pathway of mammalian cells with the Golgi apparatus playing a key role in the process. In spite of the absence of a template, the glycans synthesized by a cell are not a random collection of possible glycan structures but a distribution of specific glycans in defined quantities that is unique to each cell type (Cell type here refers to distinct cell forms present in an organism that can be distinguished based on morphological, phenotypic and/or molecular criteria.) While information to produce cell type‐specific glycans is encoded in the genome, how this information is translated into cell type‐specific glycome (Glycome refers to the quantitative distribution of all glycan structures present in a given cell type.) is not completely understood. We summarize here the factors that are known to influence the fidelity of glycan biosynthesis and integrate them into known glycosylation pathways so as to rationalize the translation of genetic information to cell type‐specific glycome.

show abstract

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Cited by 262 publications

References 66 publications

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

Translation of genome to glycome: role of the Golgi apparatus

Contact Info

Product

Resources

About