GALNT6 expression enhances aggressive phenotypes of ovarian cancer cells by regulating EGFR activity

Lin, Tzu-Chi; Chen, Syue-Ting; Huang, Min-Chuan; Huang, John; Hsu, Chia-Hao; Juan, Hsueh‐Fen; Lin, Ho‐Hsiung; Chen, Chi-Hau

doi:10.18632/oncotarget.16585

Cited by 36 publications

(35 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, an inhibitory rather than an activatory effect on EGFR signaling has been reported for NEU1 overexpression in airway cells [ 114 ]. The O -glycosylation of EGFR, mediated by GALNT2 or GALNT6, two of the 20 GalNAc transferases catalyzing the first step in O -linked biosynthesis ( Table 1 ), results in enhanced malignancy of oral [ 64 ] and ovarian cancer [ 65 ], respectively. On the other hand, GALNT2 modification of EGFR reduces malignancy of hepatocarcinoma [ 66 ].…”

Section: How Glycosylation Modulates the Activity Of Specific Recementioning

confidence: 99%

Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling

Ferreira¹,

Pucci

Venturi

et al. 2018

IJMS

View full text Add to dashboard Cite

Glycosylation is a very frequent and functionally important post-translational protein modification that undergoes profound changes in cancer. Growth and death factor receptors and plasma membrane glycoproteins, which upon activation by extracellular ligands trigger a signal transduction cascade, are targets of several molecular anti-cancer drugs. In this review, we provide a thorough picture of the mechanisms bywhich glycosylation affects the activity of growth and death factor receptors in normal and pathological conditions. Glycosylation affects receptor activity through three non-mutually exclusive basic mechanisms: (1) by directly regulating intracellular transport, ligand binding, oligomerization and signaling of receptors; (2) through the binding of receptor carbohydrate structures to galectins, forming a lattice thatregulates receptor turnover on the plasma membrane; and (3) by receptor interaction with gangliosides inside membrane microdomains. Some carbohydrate chains, for example core fucose and β1,6-branching, exert a stimulatory effect on all receptors, while other structures exert opposite effects on different receptors or in different cellular contexts. In light of the crucial role played by glycosylation in the regulation of receptor activity, the development of next-generation drugs targeting glyco-epitopes of growth factor receptors should be considered a therapeutically interesting goal.

show abstract

Section: How Glycosylation Modulates the Activity Of Specific Recementioning

confidence: 99%

Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling

Ferreira¹,

Pucci

Venturi

et al. 2018

IJMS

View full text Add to dashboard Cite

show abstract

“…We also found that GALNT6 could bind to the ATPase domain of GRP78 and stabilizes the GRP78 protein through O-glycosylations, which also contributed to proper subcellular localization and antiapoptotic function of GRP78 protein in cancer cells [28] . EGFR was also shown to be a substrate of GALNT6 in ovarian cancer cells [15] .…”

Section: Discussionmentioning

confidence: 97%

“…We also found its upregulation in pancreatic cancer cells, in which GALNT6 could cause a cadherin switch (from E-cadherin to P-cadherin) affecting cellular adhesion to the underlying matrix [14] . High GALNT6 expression was also reported to be correlated with an increased risk of recurrence, lymph node metastasis, and chemoresistance in ovarian cancer [15] . It was also shown that GALNT6 was highly upregulated in colon adenocarcinomas compared with adjacent colon tissues, implying its important role in colon carcinogenesis [8] .…”

Section: Introductionmentioning

confidence: 95%

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

et al. 2018

View full text Add to dashboard Cite

Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane–permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression–dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α–positive breast cancer patients.

show abstract

“…The high level of expression in the Basal and PMSG stages suggests that JAML might have a role in preantral follicles, especially in GC-GC or GC-oocyte interactions. GALNT6 has been shown to be essential for the activation of EGFR by phosphorylation and by modification of O-glycosylation (Lin et al, 2017). It is well known that LH-induced EGFR signaling plays a critical role in preovulatory follicle development by activating MAPK pathways and inducing the steroidogenic enzymes (Jamnongjit et al, 2005;Panigone et al, 2008;Wu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

View full text Add to dashboard Cite

Follicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

show abstract

GALNT6 expression enhances aggressive phenotypes of ovarian cancer cells by regulating EGFR activity

Cited by 36 publications

References 31 publications

Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling

Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Contact Info

Product

Resources

About