Review articlep62 as a therapeutic target for tumor
Graphical abstract
Introduction
Autophagy is a highly conserved lysosomal-mediated degradation mechanism in eukaryotic cells [1]. It is responsible for removing misfolded proteins, damaged organelles, and invading bacteria. There is a duality in the relationship between autophagy and tumorigenesis. On the one hand, in early stage of tumor, autophagy inhibits tumorigenesis through its cytoprotective effects [2]. On the other hand, many studies have shown that autophagy promotes tumor progression and survival [[3], [4], [5]].
The first identified autophagy adaptor p62 [6] is closely related to tumor development [7,8]. For example, Mallory–Denk bodies [9] and intracellular hyaline bodies [10] have been found in hepatocellular carcinoma (HCC) patients. Moreover, p62 has been identified as a morbific target for clear cell renal cell carcinoma [11]. Significantly elevated p62 expression has been observed in cancer cells [12]. Furthermore, Denk et al. presented that p62 is a good candidate as a prognostic biomarker in the tumor [13]. Therefore, p62 may be a therapeutic target for tumor.
As an autophagy adaptor, p62 recognizes ubiquitinated cargos via the ubiquitin-associated (UBA) domain and recruits them to the autophagosomal membrane via the microtubule-associated protein 1 light chain 3 (LC3)-interacting region (LIR) [14,15]. Moreover, the Phox1 and Bem1p (PB1) domain-dependent p62 self-oligomerization promotes packaging of ubiquitinated cargos [16], and packaged cargos are delivered to the proteasome [17]. In addition, as a signaling hub [18], p62 interacts with various binding partners to mediate multiple cellular functions, such as apoptosis [19], nuclear factor κB (NF-κB) activation [20], mammalian target of rapamycin complex 1 (mTORC1) activation [21], and nuclear factor erythroid 2-related factor 2 (Nrf2) activation [22]. In this review, we summarize biological functions of structural domains of p62, reported bioactive molecules targeting p62, and the relationship between p62 and tumorigenesis.
Section snippets
Structural domains of p62
As shown in Fig. 1, p62 [23] possesses multiple structural domains, including the N-terminal PB1 domain, the ZZ-type zinc finger (ZZ) domain, the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding (TB) domain, the LIR domain, the Kelch-like ECH-associated protein 1 (Keap1)-interacting region (KIR), and the C-terminal UBA domain. Through the PB1 domain, p62 forms aggregates via homodimerization, which is crucial for its degradation by autophagy [24]. In addition, p62 also
The relationship between p62 and tumorigenesis
The role of p62 in tumorigenesis is becoming increasingly complex. For example, p62 accumulation makes the genome unstable and promotes tumor development [112]. Besides, p62 in adipocytes mediates tumor-induced fat reprogramming and has its potential implications in obesity-promoted cancer [113]. Importantly, increased expression level of p62 in cancer cells is due to defective autophagy, which promotes tumorigenesis [31]. In addition, p62 appears as a signal transduction protein that not only
Concluding remarks
p62 interacts with various signaling proteins to regulate a variety of cellular functions, including (1) the activation of mTORC1 in nutrient sensing via the TB domain; (2) the activation of NF-κB during inflammation through its PB1, ZZ and TB domains; (3) the activation of Nrf2 for antioxidant response via the KIR domain; (4) the regulation of autophagy. Recently, many research results have shown that p62 plays multiple roles in tumorigenesis. p62 not only coordinates the metabolic
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This study was supported by Projects 81930100, 81773581, and 81773639 of the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province of China (no. BK20160746), National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (no. 2018ZX09711002 and 2017ZX09302003), the Priority Academic Program Development of Jiangsu Higher Education Institutions, CPU2018GY02 of Double First Class Innovation Team of China
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