Silencing of ATPase family AAA domain-containing protein 2 inhibits migration and invasion of colorectal cancer cells

Hong, Sen; Bi, Miaomiao; Yan, Zhaowei; Sun, Di; Ling, Lijun; Zhao, Chen

doi:10.4149/neo_2016_603

Cited by 17 publications

(12 citation statements)

References 36 publications

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“…The structure of ATAD2 suggests that it has functions related to genome regulation, including cell proliferation, differentiation, and apoptosis. Studies have revealed that ATAD2 is highly expressed and associated with proliferation and metastasis in several types of tumors, such as breast cancer, lung cancer, and hepatocellular carcinoma 33 – 38 . However, the expression and function of ATAD2 in PTC were unclear.…”

Section: Discussionmentioning

confidence: 99%

NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer

et al. 2018

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Nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA (lncRNA), is a core structural component of paraspeckles and is essential for paraspeckle formation. NEAT1 comprises two different isoforms: NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb). Recently, NEAT1 has been shown to have oncogenic roles and to facilitate tumorigenesis in various human cancers. However, the function of NEAT1 in papillary thyroid cancer (PTC) is not well understood. The relative expression levels of NEAT1_2, ATPase family AAA domain-containing protein 2 (ATAD2), and microRNA-106b-5p (miR-106b-5p) were assessed via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Four PTC cell lines were used to detect the relative expression of NEAT1_2. The effects of NEAT1_2 on PTC cells were studied by RNA interference approaches in vitro. The effects of NEAT1_2 on downstream proteins were detected by western blotting. The underlying mechanism was clarified by a rescue experiment, and three dual-luciferase reporter assays. NEAT1_2 expression was markedly increased in PTC tissues and the PTC cell lines (K1 and TPC1). The relative expression level of NEAT1_2 was positively associated with TNM stage and tumor size. NEAT1_2 knockdown led to a significant inhibition of growth and metastasis, and induced apoptosis in PTC cells. Knockdown of NEAT1_2 significantly inhibited malignant biological behavior by downregulating the oncogene ATAD2. In addition, NEAT1_2 could act as a competing endogenous RNA to regulate the expression of ATAD2 through downregulating miR-106b-5p. Taken together, our results indicated that NEAT1_2 is overexpressed in PTC. NEAT1_2 could function as a competing endogenous RNA to regulate ATAD2 expression by sponging miR-106b-5p in PTC. Targeting NEAT1_2 could be a promising therapeutic strategy for patients with PTC.

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Section: Discussionmentioning

confidence: 99%

NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer

et al. 2018

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“…23,24 Once initiated, ATAD2 expression leads to several positive feedback loops, dependent on tissue type, the products of which will further upregulate ATAD2, 16 cell proliferation, and survival genes. ATAD2 overexpression is associated with a myriad of unrelated cancers, including breast, 20,23,[25][26][27][28] colorectal, [29][30][31] endometrial [32][33][34] gastric, 31,35,36 hepatocellular carcinoma, [37][38][39][40] lung, 25,41,42 ovarian, 43,44 and prostate. 16,45,46 Up regulation of ATAD2 is often correlated with poor patient outcomes, and can be used as prognostic marker.…”

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confidence: 99%

Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain

et al. 2018

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The ATPase family, AAA domain-containing protein 2 (ATAD2) has a C-terminal bromodomain, which functions as a chromatin reader domain recognizing acetylated lysine on the histone tails within the nucleosome. ATAD2 is overexpressed in many cancers and its expression is correlated with poor patient outcomes, making it an attractive therapeutic target and potential biomarker. We solved the crystal structure of the ATAD2 bromodomain and found that it contains a disulfide bridge near the base of the acetyllysine binding pocket (Cys1057-Cys1079). Sitedirected mutagenesis revealed that removal of a free C-terminal cysteine (C1101) residue greatly improved the solubility of the ATAD2 bromodomain in vitro. Isothermal titration calorimetry experiments in combination with the Ellman's assay demonstrated that formation of an intramolecular disulfide bridge negatively impacts the ligand binding affinities and alters the thermodynamic parameters of the ATAD2 bromodomain interaction with a histone H4K5ac peptide as well as a small molecule bromodomain ligand. Molecular dynamics simulations indicate that the formation of the disulfide bridge in the ATAD2 bromodomain does not alter the structure of the folded state or flexibility of the acetyllysine binding pocket. However, consideration of this unique structural feature should be taken into account when examining ligandbinding affinity, or in the design of new bromodomain inhibitor compounds that interact with this acetyllysine reader module. K E Y W O R D S acetyllysine, ATAD2, bromodomain inhibitor, chromatin reader domain, disulfide bridge, epigenetics, histone, post-translational modification

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“…The reduction or loss of E-cadherin is a key factor in the occurrence of EMT 31 . A previous study showed that silencing ATAD2 inhibited the migration and invasion of colorectal cancer cells by suppressing EMT 13 . Similar studies indicated that the inhibition of EMT in renal cell carcinoma cells is regulated by ATAD2 14 .…”

Section: Discussionmentioning

confidence: 98%

“…After undergoing EMT, which is related to tumor invasion, metastasis and the development of a cancer stem cell (CSC) phenotype; tumor cells acquire invasive potential, infiltrate into the surrounding matrix, and form a microenvironment that promotes tumor growth and metastasis 12 . It has been reported that suppression of EMT is related to the downregulation of ATAD2 in colorectal cancer 13 and renal cell carcinoma 14 . These results suggest that ATAD2 may be a biomarker of tumor proliferation and metastasis, as well as a prognostic factor for many human tumors.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ATAD2 indicates Poor Prognosis in Oral Squamous Cell Carcinoma

Wang

et al. 2020

Int. J. Med. Sci.

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ATPase family AAA domain-containing protein 2 (ATAD2) is highly expressed in a variety of malignancies and can promote the proliferation of tumor cells and inhibit their differentiation. However, the expression of ATAD2 and its related mechanism in oral squamous cell carcinoma (OSCC) are still unknown. Immunohistochemical staining of ATAD2, cancer stem cells (CSCs) markers and immune checkpoint molecules was conducted on human OSCC specimens to determine the expression levels of these proteins and their correlations with the clinicopathological characteristics of ATAD2 in OSCC. Moreover, the role of ATAD2 in cell proliferation, apoptosis, migration and epithelial-mesenchymal transition (EMT) were assessed by silencing ATAD2 in vitro . Immunohistochemical analysis revealed that ATAD2 expression in OSCC tissues was markedly higher than that in adjacent dysplastic tissues and normal mucosal tissues. Overexpression of ATAD2 was related to poor overall survival in OSCC patients. In addition, the protein expression of ATAD2 was notably correlated with the expression of B7-H4, PD-L1, CMTM6, Slug and ALDH1 in human OSCC. ATAD2 knockdown arrested the cell cycle, promoted the apoptosis, and inhibited the proliferation, migration, and EMT of OSCC cells. In conclusion, these findings revealed that ATAD2 is highly expressed in OSCC and can act as a poor prognostic indicator.

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Silencing of ATPase family AAA domain-containing protein 2 inhibits migration and invasion of colorectal cancer cells

Cited by 17 publications

References 36 publications

NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer

NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer

Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain

Overexpression of ATAD2 indicates Poor Prognosis in Oral Squamous Cell Carcinoma

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