GalNAc-T4 putatively modulates the estrogen regulatory network through FOXA1 glycosylation in human breast cancer cells

Abstract

GALNT4 belongs to a family of N-acetylgalactosaminyltransferases, which catalyze the transfer of GalNAc to Serine or Threonine residues in the initial step of mucin-type O-linked protein glycosylation. This glycosylation type is the most complex post-translational modification of proteins, playing important roles during cellular differentiation and in pathological disorders. Most of the breast cancer subtypes are estrogen receptor positive, and hence, the estrogen pathway represents a key regulatory network. We investigated the expression of GalNAc-T4 in a panel of mammary epithelial cell lines and found its expression is associated with the estrogen status of the cells. FOXA1, a key transcription factor, functions to promote estrogen responsive gene expression by acting as a cofactor to estrogen receptor alpha (ERα), but all the aspects of this regulatory mechanism are not fully explored. This study found that knockdown of GALNT4 expression in human breast cancer cells attenuated the protein expression of ERα, FOXA1, and Cyclin D1. Further, our immunoprecipitation assays depicted the possibility of FOXA1 to undergo O-GalNAc modifications with a decrease of GalNAc residues in the GALNT4 knockdown cells and also impairment in the FOXA1-ERα association. Rescuing GALNT4 expression could restore the interaction as well as the glycosylation of FOXA1. Together, these findings suggest a key role for GalNAc-T4 in the estrogen pathway through FOXA1 glycosylation.

Altered expression of different GalNAc-transferases is associated with disease progression and poor prognosis in women with high-grade serous ovarian cancer

“…Thus, concerning GALNT2, only one study is suggestive for a possible oncogenic role of this transferase in oral cancer (26), while other studies in different cancer types, including neuroblastoma, liver and gastric cancer, are strongly supportive for a role of GALNT2 in suppressing tumorigenesis (27)(28)(29). GALNT4 has also displayed discrepant roles in different cancers, as an implication of GALNT4 in breast carcinogenesis has been repeatedly demonstrated (30)(31)(32); however low GALNT4 expression was associated with poor PFS and overall survival of clear cell renal cell carcinoma patients (33). GALNT6 has been extensively studied for its implication in the malignant transformation and metastasis of epithelial cancers (34)(35)(36)(37), and especially in breast cancer (38)(39)(40), where GALNT6 has been suggested as a novel marker for breast cancer detection and potential therapeutic target (41)(42)(43)(44).…”

Reduced expression of ppGalNAc‐T4 promotes proliferation of human breast cancer cells

“…Notably ppGalNAc‐T4 overexpression suppressed breast cancer cell proliferation, colony formation, and cell cycle progression in MDA‐MB‐231 cells; on the contrary, ppGalNAc‐T4 knock out produced promoting effects on proliferation, colony formation, and cell cycle progression in MCF7 cells. In Niang et al's (2016) previous study, knockdown of ppGalNAc‐T4 expression in human T47D breast cancer cells attenuated the expression of Cyclin D1 and thus cell growth. The data in the current studies show the opposite which might be caused by cell‐line specific.…”

The polypeptide N‐acetylgalactosaminyltransferase 4 exhibits stage‐dependent expression in colorectal cancer and affects tumorigenesis, invasion and differentiation

“…Considering that the colony formation and sphere formation abilities could partially indicate the tumorigenic potentials of tumor cells, we think that upregulation of ppGalNAc-T4 at the early stage of CRC may contribute to its tumorigenesis. Like ppGalNAc-T4, ppGalNAc-T1 and ppGal-NAc-T14 have also been implicated in the regulation of cell tumorigenesis in different types of carcinomas including bladder cancer and breast cancer [40][41][42]. These observations suggest that different ppGalNAc-Ts may have similar functions but are associated with different tumors.…”