Abstract
Enhanced glycolysis is a hallmark of breast cancer. In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. Together with glucose, methylglyoxal (MGO), a byproduct of glycolysis, is considered the main glycating agent. MGO is highly diffusible, enters the nucleus, and can react with easily accessible lysine- and arginine-rich tails of histones. Glycation adducts on histones undergo oxidization and further rearrange to form stable species known as advanced glycation end-products (AGEs). This modification alters nucleosomes stability and chromatin architecture deconstructing the histone code. Formation of AGEs has been associated with cancer, diabetes, and several age-related diseases. Recently, DJ-1, a cancer-associated protein that protects cells from oxidative stress, has been described as a deglycase enzyme. Although its role in cell survival results still controversial, in several human tumors, its expression, localization, oxidation, and phosphorylation were found altered. This work aimed to explore the molecular mechanism that triggers the peculiar cellular compartmentalization and the specific post-translational modifications (PTM) that, occurring in breast cancer cells, influences the DJ-1 dual role. Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. Notably, this threonine is in addition to histidine 126, a key residue involved in the formation of catalytic triade (glu18-Cys106-His126) inside the glioxalase active site of DJ. Interestingly, we found that pharmacological modulation of Akt pathway induces a functional tuning of DJ-1 proteoforms, as well as their shuttle from cytosol to nucleus, pointing out that pathway as critical in the development of DJ-1 pro-tumorigenic abilities. Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. In normal conditions, DJ-1 acts as a redox-sensitive chaperone and as an oxidative stress sensor. In cancer cells, glycolytic rewiring, inducing increased reactive oxygen species (ROS) levels, enhances AGEs products. Alongside, the moderate increase of ROS enhances Akt signaling that induces DJ-1-phosphorylation. When phosphorylated DJ-1 increases its glyoxalase activity, the level of AGEs on histones decreases. Therefore, phospho-DJ-1 prevents glycation-induced histones misregulation and its Akt-related hyperactivity represents a way to preserve the epigenome landscape sustaining proliferation of cancer cells. Together, these results shed light on an interesting mechanism that cancer cells might execute to escape the metabolic induced epigenetic misregulation that otherwise could impair their malignant proliferative potential.
Highlights
Metabolic rewiring is the main hallmark of several types of cancer
We introduce a new order of complexity for DJ-1 protein function, providing evidence that the glyoxalase activity, determinant to counteract aging triggered by advanced glycation end products (AGEs) formation on histone proteins, may be modulated by mitogenic pathway
Metabolic rewiring is a key hallmark of cancer and breast cancer cells exhibit a clear shift toward glycolytic metabolism
Summary
Metabolic rewiring is the main hallmark of several types of cancer. Cancer cells rewire their metabolic program to meet the energetic requirements sustaining proliferation, survival, and invasion.The comprehension of the pathway triggering metabolic changes, that sustain the high energetic and anabolic requirements of the malignant phenotype, might greatly improve the understanding of tumor biology and the development of targeted therapies.In breast cancer cells, the Warburg effect is a common feature, shared by all breast cancer subtypes [1]. Metabolic rewiring is the main hallmark of several types of cancer. Cancer cells rewire their metabolic program to meet the energetic requirements sustaining proliferation, survival, and invasion. The comprehension of the pathway triggering metabolic changes, that sustain the high energetic and anabolic requirements of the malignant phenotype, might greatly improve the understanding of tumor biology and the development of targeted therapies. The switch toward aerobic glycolysis accounts for the production of biohazard products as Glyoxal and Methylglyoxal (MGO) able to react with peculiar amino acids, including arginines and lysines.
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