Epigenetic high regulation of ATAD2 regulates the Hh pathway in human hepatocellular carcinoma

Abstract

ATAD2 is associated with many cellular progresses such as cell growth, differentiation and apoptosis. Some studies suggest ATAD2 is highly expressed in cancer cells. In our previous studies, we found that ATAD2 is highly expressed in HCC tissues, compared with adjacent normal tissues, and patients with high expression of ATAD2 had a poorer prognosis. Moreover, we found mir-372 can regulate the expression of ATAD2 in HCC cell lines. We also detected a relationship between the mRNA expression of ATAD2 and Ptch1 by gene microarray. Here, we completed the function studies of ATAD2 in vivo and in vitro, and tested whether ATAD2 could regulate the Hh pathway. ATAD2 and Hh pathway protein expressions in 80 HCC specimens were examined by immunohistochemistry (IHC). The mRNA expression of ATAD2 and Hh pathway members in paired-HCC tissues and cell lines were, respectively, analyzed using quantitative PCR. ATAD2‑RNAi was transduced into HCCLM3 and Huh7 cells, using a lentiviral vector. The effect of ATAD2 in HCC cell lines on cell cycle and apoptosis were evaluated by flow cytometry. Tumorigenicity experiments in nude mice were performed to test the function of ATAD2 in vivo. Pharmacological regulation of Hh signaling was performed to test the relation between the ATAD2 and Hh pathways and C-myc. We found that ATAD2 and Ptch1 were both highly expressed in HCC tissues, compared with paired normal hepatic tissues. In addition, we found that ATAD2 could affect the expression of the Hh pathway by PCR and western blot anaysis in HCC cell lines, by observing the outcome before and after transfection. We speculate that ATAD2 cooperates with the MYC gene to regulate the expression of SMO and Gli, activating the Hh pathway and inducing an active feedback of the Hh pathway.

ATAD2 is associated with malignant characteristics of pancreatic cancer cells

“…ATAD2 promotes proliferation and survival of breast cancer cells by regulating the expression of B-Myb, enhancer of zeste 2 polycomb repressive complex 2 subunit or nuclear receptor coactivator 3 (16). High expression of ATAD2 has also been reported in endometrial carcinoma, hepatocellular carcinoma, cervical cancer and lung cancer (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). These studies clearly demonstrate that ATAD2 is critical for cancer progression and is a promising target for cancer therapy.…”

Long noncoding RNA PCAT-14 induces proliferation and invasion by hepatocellular carcinoma cells by inducing methylation of miR-372

“…ATAD2 is one of the target genes of miR-372, and regulates the Hh pathway to influence HCC cell proliferation and metastasis [23, 24]. To investigate the role of PCAT-14 in ATAD2 and Hh signaling, we altered the expression of PCAT-14 in SMMC7721 and HepG2 cells, and evaluated gene and protein levels of ATAD2 and Hh pathway key proteins (PTCH-1, SMO, and Gli2).…”

<p>Knockdown of ATAD2 Inhibits Proliferation and Tumorigenicity Through the Rb-E2F1 Pathway and Serves as a Novel Prognostic Indicator in Gastric Cancer</p>

“…ATAD2 can function as a cofactor with other transcription factors, such as E2F, 7 and it can also improve the transcription activity of c-Myc 13,14 to regulate specific sets of genes that have oncogenic functions. Through c-Myc and E2F transcription factors, ATAD2 increases the expression of proliferation-related and anti-apoptotic genes in many different types of cancer.…”

“…Through c-MYC and E2F transcription factors, ATAD2 increases the expression of proliferation-related and anti-apoptotic genes in many different types of cancer. 7,13,14 However, there have been no studies concerning the gene functions related to ATAD2 in GC.…”