Chromium is a naturally occurring metallic element found in the earth's crust, which is widely used in steel manufacturing, painting and industrial chrome plating. Two oxidation states of chromium are biologically and environmentally relevant in the presence of water and oxygen [1]. Cr (III) is a beneficial micronutrient to human body. However, compounds of hexavalent chromium [Cr (VI)] are common environmental and occupational hazards which usually result in pulmonary diseases [2]. When inhaled and potentially ingested, Cr (VI) can induce cellular toxicity, DNA damage, and oxidative stress [3]. Accumulating evidences have recognized Cr (VI) as mutagen and carcinogen in rodents [4]. Epidemiological studies indicated that exposure to Cr (VI) increased the risk for lung cancer and Cr (VI) is recognized as a human carcinogen by International Agency for Research on Cancer (IARC) [5]. Reactive oxygen species (ROS) has been identified to play a major role in Cr (VI) carcinogenesis, but the underlying mechanism is unclear.

High mobility group A (HMGA) family is composed of HMGA1a, HMGA1b and HMGA2 [6]. They are non-histone chromosomal proteins, which are characterized by highly conserved DNA-binding motifs called “AT-hooks” [7]. HMGA2 is a structural transcription factor, which is involved in gene transcription regulation, chromatin condensation and DNA damage repair [8]. As a transcription factor, HMGA2 plays an important role in obtaining the phenotype of cancer stem cells and the degree of malignant tumors. Increasing evidences indicated that HMGA2 are abundant in embryogenesis and malignant neoplasms, such as pancreas, breasts, and lungs [9]. So far, the precise role of HMGA2 in malignant transformation is still not clear.

In cancer cells, activating transcription factor 4 (ATF4) is frequently aberrantly expressed [10]. ATF4 belongs to the activating transcription factor/cAMP responsive element binding protein family, and is a transcription factor which is phosphorylated on serine residues by protein kinases [11]. Usually, ATF4 is induced by the increase in unfolded proteins and amino acid starvation, and plays a well-known role in ER stress response. Thus, ATF4 is considered as one of the most robustly up-regulated targets upon ER stress [12]. Upon ER stress, eukaryotic translation initiating factor 2 α (eIF2α) which is the upstream effector of the unfolded protein response (UPR), is phosphorylated by PERK kinase [13]. Then the phosphorylated eIF2α can promote the translation of ATF4 to the nucleus to transcriptionally regulate genes involved in apoptosis [14]. On the one hand, during long-term external environmental stimulation, ATF4 can promote apoptosis [15], which exert its beneficial effects of anti-tumor. On the other hand, ATF4 has been identified as a stress-induced transcriptional factor, which controls the expression of a series of genes that regulate signaling pathways during hypoxia, redox imbalance [16] and amino acid deprivation [17]. Notably, in cancer cells, increasing of the expression of ATF4 can eliminate the stress induced by nutrient limitation and rapid proliferation [18]. In addition, ATF4 was also demonstrated to enhance aerobic glycolysis and oxidative phosphorylation (OXPHOS) by mTORC1, and maintain growth and metabolism of cancer cells [19]. Mitochondria are the main cellular energy source for the production of adenosine triphosphate (ATP) through aerobic respiration and OXPHOS under normal physiological conditions [20]. However, in most cancer cells, glycolysis rather than OXPHOS is the main energy metabolic pathway for ATP supply [21]. Although glycolysis is far less efficient than OXPHOS, cancer cells display a drastically high glycolytic rate to increase glucose uptake for ATP production [22]. Consequently, in cancer cells, glucose uptake and glycolysis increased to yield much more intermediate glycolytic metabolites and pyruvate [23], and most glycolysis-derived pyruvate is diverted to lactate and mitochondrial OXPHOS is reduced, even in the case of sufficient oxygen [24]. This phenomenon is known as the Warburg effect [25].

In our previous study, we found that HMGA2 played an important role in Cr (VI)-induced cell growth by elevating autophagy [26] and ATF4-mediated autophagy-dependent glycolysis was involved in Cr (VI)-induced cell migration of A549 cells by attenuation of apoptosis [27]. So, in this study, the interaction of HMGA2 and ATF4 in Cr (VI)-mediated glycolysis and OXPHOS was investigated. The results indicated that ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced glycolysis and inhibited OXPHOS by binding to the promoter of the ATF4 gene to increase transcription of ATF4.