Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. its DNA-binding properties (20), and HMGA2 Polaprezinc SUMOylation may promote promyelocytic leukemia (PML) protein degradation (21). However, whether PTM functions in the regulation of HMGA2 expression remains largely unknown. Mammalian hepatitis B X-interacting protein (HBXIP), also known as LAMTOR5 (22), is usually a conserved 18-kDa protein, which was identified initially based on its binding to the C-terminus of hepatitis B computer virus X proteins (23). HBXIP is usually expressed in nearly all tissues (24). It can function as a cofactor of survivin to control cell apoptosis and regulate centrosome duplication and cytokinesis to mediate cell growth (24,25). Additionally, HBXIP can serve as a regulatory component required for the activation of mammalian target of rapamycin complex 1 via amino acids (22). Our group has reported that HBXIP is usually highly expressed in breast carcinoma and that it acts as an oncogenic transcriptional coactivator of multiple transcription factors, such as c-Myc, LXR, Sp1?and E2F1 to promote breast cancer growth and metastasis (26C29). Moreover, it supports the migration of breast malignancy cells through GCN5-mediated modulation of microtubule acetylation (30). Our study has revealed that HBXIP as an important oncoprotein can regulate PTMs of some transcription factors. For instance, HBXIP can induce the acetylation of transcription factor HOXB13 to prevent HOXB13 degradation in the promotion of tamoxifen resistance of breast malignancy (31). In addition, HBXIP can increase the phosphorylation levels of c-Fos through activating ERK1/2, which is a benefit for the nuclear localization of c-Fos in breast malignancy (32). One study found that the abnormal expression of HBXIP was associated with poor prognosis in ESCC (33). Accordingly, in the present study we are interested in whether HBXIP is usually involved in HMGA2 PTM in ESCC development. Aspirin (ASA), a nonsteroidal anti-inflammatory drug, displays anti-cancer effect and has been applied in colorectal cancer therapy (34). Substantial evidence indicates that regular aspirin use is useful for the reduction of incidence, mortality and distant metastasis of cancers including breast malignancy, liver malignancy, and colorectal cancer (35C37). Several epidemiologic studies have proven that the use of aspirin and other nonsteroidal anti-inflammatory drugs protects against the development of esophageal cancer (38,39). We have recently revealed that aspirin can target HBXIP to inhibit HBXIP/HOXB13 axis, overcoming tamoxifen resistance in breast malignancy (31). Based on these previous findings, we focus on the investigation of the role of aspirin in HBXIP-associated ESCC. In the present study, we explored the function and regulation of HMGA2 in the development of ESCC. HBXIP enhances HMGA2 acetylation at the lysine 26 residue (K26) through the Akt pathway-induced PCAF phosphorylation and activation in ESCC. HMGA2 K26 acetylation functionally enhances its DNA binding ability on the target genes and Polaprezinc blocks its ubiquitination and proteasomal degradation, thus leading to HMGA2 accumulation and carcinogenesis. Intriguingly, aspirin can suppress ESCC growth through repressing HBXIP and HMGA2. Thus, our studies identify a novel regulatory mechanism of HMGA2 in ESCC growth, which probably provides an effective strategy for ESCC therapy. MATERIALS AND METHODS Tissue specimens The ESCC tissue microarray made up of 151 primary ESCC tissues and 43 normal esophageal tissues with information of patients’ overall survival and disease-free survival was acquired from Shantou University Medical College between February 2011 and November 2016. The patient records are presented in Supplementary Table S1. The other two ESCC tissue microarrays (Catalog No.: Es-kx03c and Catalog No.: Es-kx14c) made up of 124 cases of human ESCC tissues, two cases Polaprezinc of human esophagus basal cell carcinoma tissues and 10 cases of normal esophagus tissues in total were purchased from Aomeibio Company (Xian, China). The clinical characteristics are presented in Supplementary Tables S5 and S6 respectively. All samples were approved by Ethics Committee of Hospital providing tissues. Rock2 Written informed consent was obtained from patients before samples were collected. All specimens, including tumor tissues of ESCC patients and normal esophageal tissues, were obtained during surgery. Cell culture and reagents The ESCC cell lines KYSE2, KYSE180, KYSE450, KYSE510 and the human embryonic kidney cell line 293T (HEK293T) were obtained from the American Type Culture Collection (ATCC). ESCC cell lines were cultured in RPMI 1640 (Gibco, USA) supplemented with 10% fetal bovine serum (FBS; Gibco). HEK293T.

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