Abstract
Glycosylation, one of the most fundamental posttranslational 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. 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 Nglycans from chemosensitive/non-metastatic cells
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. 5-AZA-dC-treated cells displayed an
increase in migration, with a greater effect seen in chemosensitive cell lines. Western blots showed an increase in
apoptotic and senescence (p21) markers in all 5-AZAdCtreated 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.
Moreover, increased expression of ST3GAL4 was
associated with poor recurrence free survival in ovarian
and lymph node positive TNBC patients. 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 chemo-sensitive and
chemo-resistant ovarian and breast cancer cells.
Keywords
Glycosylation, Biochemistry
Biochemists are interested, for example, in mechanisms of brain function, cellular multiplication and differentiation, communication within and between cells and organs, and the chemical bases of inheritance and disease. The biochemist seeks to determine how specific molecules such as proteins, nucleic acids, lipids, vitamins, and hormones function in such processes. Particular emphasis is placed on the regulation of chemical reactions in living cells.
Biochemistry is both life science and a chemical science - it explores the chemistry of living organisms and the molecular basis for the changes occurring in living cells. It uses the methods of chemistry,
"Biochemistry has become the foundation for understanding all biological processes. It has provided explanations for the causes of many diseases in humans, animals and plants."
physics, molecular biology, and immunology to study the structure and behaviour of the complex molecules found in biological material and the ways these molecules interact to form cells, tissues, and whole organisms.
