5-AZA-dC induces epigenetic changes associated with modified glycosylation of secreted glycoproteins and increased EMT and migration in chemo-sensitive cancer cells.pdf (2.47 MB)
Download file

5-AZA-dC induces epigenetic changes associated with modified glycosylation of secreted glycoproteins and increased EMT and migration in chemo-sensitive cancer cells

Download (2.47 MB)
journal contribution
posted on 24.11.2022, 16:36 authored by Gordon Greville, Esther Llop, Jane Howard, Stephen MaddenStephen Madden, Antoinette S Perry, Rosa Peracaula, Pauline M Rudd, Amanda McCann, Radka Saldova

Background: Glycosylation, one of the most fundamental post-translational modifications, is altered in cancer and is subject in part, to epigenetic regulation. As there are many epigenetic-targeted therapies currently in clinical trials for the treatment of a variety of cancers, it is important to understand the impact epi-therapeutics have on glycosylation.

Results: Ovarian and triple negative breast cancer cells were treated with the DNA methyltransferase inhibitor, 5-AZA-2-deoxycytidine (5-AZA-dC). Branching and sialylation were increased on secreted N-glycans from chemo-sensitive/non-metastatic cell lines following treatment with 5-AZA-dC. These changes correlated with increased mRNA expression levels in MGAT5 and ST3GAL4 transcripts in ovarian cancer cell lines. Using siRNA transient knock down of GATA2 and GATA3 transcription factors, we show that these regulate the glycosyltransferases ST3GAL4 and MGAT5, respectively. Moreover, 5-AZA-dC-treated cells displayed an increase in migration, with a greater effect seen in chemo-sensitive cell lines. Western blots showed an increase in apoptotic and senescence (p21) markers in all 5-AZA-dC-treated cells. The alterations seen in N-glycans from secreted glycoproteins in 5-AZA-dC-treated breast and ovarian cancer cells were similar to the N-glycans previously known to potentiate tumour cell survival.

Conclusions: While the FDA has approved epi-therapeutics for some cancer treatments, their global effect is still not fully understood. This study gives insight into the effects that epigenetic alterations have on cancer cell glycosylation, and how this potentially impacts on the overall fate of those cells.

Funding

Science Foundation Ireland Starting Investigator Research grant (SFI SIRG) under grant number 13/SIRG/2164

Spanish Ministry of Economy and Competitivity (grant BIO 2015–66356-R)

University of Girona (grant MPCUdG2016/028)

University College Dublin (UCD PhD Advance Core Scheme)

History

Comments

The original article is available at https://clinicalepigeneticsjournal.biomedcentral.com/

Published Citation

Greville G. et al. 5-AZA-dC induces epigenetic changes associated with modified glycosylation of secreted glycoproteins and increased EMT and migration in chemo-sensitive cancer cells. Clin Epigenetics. 2021;13(1):34.

Publication Date

12 February 2021

PubMed ID

33579350

Department/Unit

  • Data Science Centre

Publisher

BioMed Central

Version

  • Published Version (Version of Record)