Abstract
O-linked N-acetylglucosamine transferase (OGT) expression is increased in various cancer types, indicating the potential importance of O-GlcNAcylation in tumorigenesis. Secretory clusterin (sCLU) is involved in cancer cell proliferation and drug resistance, and recently, liver X receptors (LXRs) and sterol response element binding protein-1 (SREBP-1) were reported to regulate sCLU transcription. Here, we found that sCLU is significantly increased in cervical cancer cell lines, which have higher expression levels of O-GlcNAc and OGT than keratinocytes. OGT knockdown decreased expression of LXRs, SREBP-1 and sCLU through hypo-O-GlcNAcylation of LXRs. Additionally, treatment with Thiamet G, O-GlcNAcase OGA inhibitor, increased expression of O-GlcNAcylation and sCLU, and high glucose increased levels of LXRs, SREBP-1 and sCLU in HeLa cells. Moreover, OGT knockdown induced G0/G1 phase cell cycle arrest and late apoptosis in cisplatin-treated HeLa cells, and decreased viability compared to OGT intact HeLa cells. Taken together, these findings suggest that OGT, O-GlcNAcylated LXRs, and SREBP-1 increase sCLU expression in cervical cancer cells, which contributes to drug resistance.
Highlights
Clusterin (CLU) is a highly conserved glycoprotein expressed ubiquitously in various tissue types, and has been implicated in aging, cancer progression, and several metabolic diseases [1, 2]
We found that levels of Secretory clusterin (sCLU) and O-linked N-acetylglucosamine transferase (OGT) mRNA expression were increased in HeLa, SiHa, C33A compared to HaCaT cells (Supplementary Figure 1)
These data suggest that OGT, O-GlcNAc, and sCLU expression is increased in cervical cancer cell lines and cervical cancer
Summary
Clusterin (CLU) is a highly conserved glycoprotein expressed ubiquitously in various tissue types, and has been implicated in aging, cancer progression, and several metabolic diseases [1, 2]. SCLU acts as a molecular chaperone and promotes cell survival [5, 6], while sCLU is partially responsible for increased resistance of cancer cells to several chemotherapies due to its pro-survival functions [7,8,9,10]. CLU expression is regulated by metabolic signals, such as sterol regulatory element binding protein-1 (SREBP-1) [11,12,13], and hyperglycemia induces sCLU expression through the SREBP response element (SRE) but not by carbohydrate responsive element binding protein (ChREBP) in primary hepatocytes and hepatoma cell lines [14]. The role of O-GlcNAcylation in tumorigenesis and progression is becoming clearer, but several unanswered questions, such as its role in drug resistance, still remain
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