Hyperglycemia and aberrant O-GlcNAcylation: contributions
to tumor progression
Rafaela Muniz de Queiroz
Bruno da Costa Rodrigues
Adriane R. Todeschini
Wagner B. Dias
Received: 28 October 2017 /Accepted: 26 December 2017 /Published online: 11 January 2018
Springer Science+Business Media, LLC, part of Springer Nature 2018
A number of cancer types have shown an increased prevalence and a higher mortality rate in patients with hyperglycemic
associated pathologies. Although the correlation between diabetes and cancer incidence has been increasingly reported, the
underlying molecular mechanisms beyond this association are not yet fully understood. Recent studies have suggested that high
glucose levels support tumor progression through multiple mechanisms that are hallmarks of cancer, including cell proliferation,
resistance to apoptosis, increased cell migration and invasiveness, epigenetic regulation (hyperglycemic memory), resistance to
chemotherapy and altered metabolism. Most of the above occur because hyperglycemia through hexosamine biosynthetic
pathway leads to aberrant O-GlcNAcylation of many intracellular proteins that are involved in those mechanisms.
Deregulated O-GlcNAcylation is emerging as a general feature of cancer. Despite strong evidence suggesting that aberrant O-
GlcNAcylation is or may be involved in the acquisition of all cancer hallmarks, it remains out of the list of the next generation of
emerging hallmarks. Here, we discuss some of the current understanding on how hyperglycemia affects cancer cell biology and
how aberrant O-GlcNAcylation stands in this context.
Hexosamine biosynthetic pathway
Hyperglycemia is defined as excessive blood glucose
levels. A number of medical conditions can cause hyper-
glycemia, including diabetes mellitus (DM) (Dobbs et al.
1975), obesity (Martyn et al. 2008), pancreatitis (Fogar
et al. 1998), chronic stress (Mechanick 2006), and pan-
creatic cancer (He and Yuan 2014). Hyperglycemia often
leads to a diagnosis of diabetes, a chronic disorder of
insulin secretion and/or resistance (Type 1 DM/Type 2
DM). The number of adults living with diabetes has
reached 422 million in 2016 and according to the world
health organization; 1.5 million people die from this dis-
ease every year (WHO 2016).
The Diabetes Control and Complications Trial (DCCT)
and its follow-up Epidemiology of Diabetes Interventions
and Complications (EDIC) study, reported that hyperglycemia
is a key pathological factor involved in diabetic complications
(Writing Team for the Diabetes et al. 2003). A high percentage
of diabetic patients undergo microvascular and macrovascular
complications such as diabetic retinopathy, nephropathy and
neuropathy, atherosclerosis, hypertension and stroke
(Beckman et al. 2002; Boulton et al. 2005; Cheung et al.
2010; Sowers et al. 2001; Ziyadeh and Sharma 2003). In ad-
dition to the vascular complications, DM also increases the
risk of cancer (Biadgo and Abebe 2016; Lipscombe et al.
2006; Meier and Giese 2015; Vigneri et al. 2009). Having
DM means worse prognosis in patients with many types of
cancer (Coughlin et al. 2004; Giovannucci et al. 2010; Vigneri
et al. 2009). Hyperglycemia and/or high glucose condition
affect different types of tumors, including breast (Flores-
Lopez et al. 2016), liver (Luo et al. 2011), endometrial (Han
et al. 2015), colon (Meier and Giese 2015; Vasconcelos-Dos-
Santos et al. 2017), lung (Alisson-Silva et al. 2013), prostate
Andréia Vasconcelos-dos-Santos and Rafaela Muniz de Queiroz contrib-
uted equally to this work.
* Wagner B. Dias
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do
Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Journal of Bioenergetics and Biomembranes (2018) 50:175–187