DJ-1 Proteoforms in Breast Cancer Cells: The Escape of Metabolic Epigenetic Misregulation

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.

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

“…Recently, DJ-1 has been described as a key histone deglycase that rescues glycation-induced damage [9,10]. When phosphorylated, DJ-1 increases its glyoxalase activity preventing glycation-induced histones mis-regulation and preserving the epigenome landscape and, in the case of cancer cells, sustaining proliferation [11]. More recently, DJ-1 has been shown to mediate the development of multiple drug resistance (i.e., cancer cells) [12] by activating the PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating anti-apoptotic genes [13].…”

Cancer Metabolism as a New Real Target in Tumor Therapy

“…They postulated that excreted lactate by glycolytic cancer cells inhibits SIRT1 in adjacent tumor and normal cells, causing histone H3 hyperacetylation and tumor cell aggressiveness. A link between histone modifications and glycolysis was also described by Scumaci and colleagues [15]. In particular, they defined a histone protein modification, namely, advanced glycation end products (AGE), due to the Warburg effect.…”

ASF1 activation PI3K/AKT pathway regulates sexual and asexual development in filamentous ascomycete

“…Previous studies revealed that DJ-1 was involved in multiple biological functions in mammals (Hijioka et al, 2017; Scumaci et al, 2020; Mencke, 2021; Nakamura et al, 2021). However, DJ-1 regulation of sexual and asexual differentiation in mammals, plants and fungi was poorly understood.…”

“…DJ-1, named as PARK7, is first reported to associated with Parkinson’s disease (PD) (Bonifati et al 2012) and then verifies to be an oncogene for mediating the regulation of numerous types of cancer (Bai et al, 2012; Chen et al, 2012; Scumaci et al, 2020). DJ-1 is an essential regulator of multiple cellular processes, including anti-oxidative stress, anti-apoptotic effects, and protein degradation (Taira et al, 2004; Mukherjee et al, 2015; Hijioka et al, 2017).…”