Tumor-Promoting ATAD2 and Its Preclinical Challenges

Abstract

ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2's bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.

Keywords: ATAD2; bromodomain; malignant tumor; pharmacology.

Figure 1

Schematic diagram of the ATAD2 domain structure and the partial functions of the AAA-ATAD2 and bromodomain.

Figure 2

Role of ATAD2 in digestive system malignant tumors. lncRNA PCAT-14 and CRND inhibit, respectively, miR-372 and miR126-5p to promote the transcription of ATAD2. ATAD2 promotes tumor cell proliferation, invasion, migration, and tumorigenesis through the pRb-E2F1 pathway, HH pathway, ERO1L/G3BP2, and APC/β-catenin. ATAD2 increases the differential expression of NCOA1/PRMT1 via ESR1, which affects the acetylation level of histones to promote tumorigenesis. ATAD2 represses miR-520a and promotes the expression of VEGFA and E2F2, which are associated with tumor angiogenesis and tumor cell proliferation, separately. ATAD2 promotes the expression of Snail and Smad3 via C/EBPβ/ TGF-β1, Smad3 facilitates tumor metastasis, and Snail enhances it by EMT. ATAD2 also promotes proliferation and inhibits apoptosis, respectively, via the E2F2 and p53/p38 pathways in tumor cells.

Figure 3

Partial roles of ATAD2 in other types of malignant tumors. lncRNA NEAT1_2 and lncRNA MALAT1 promote ATAD2 expression by repressing miR-106b-5p and miR-655-3p, respectively. Moreover, METTL3 promotes ATAD2 expression, but miR-186 negatively regulates ATAD2 expression. ATAD2 promotes tumor cell proliferation and survival by regulating cell cycle, nucleic acid metabolism, PD-L1, B7-H4, ALDH1 Slug, and CMTM6 proteins.