ONCOLOGY LETTERS 15: 2743-2748, 2018 Functions of nuclear actin‑binding proteins in human cancer (Review) XINYI YANG1,2 and YING LIN1,2 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation; 2Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China Received February 16, 2017; Accepted November 10, 2017 DOI: 10.3892/ol.2017.7658 Abstract. Nuclear actin-binding proteins (ABPs) perform that contain actin-binding domains that interact with actin. distinguishable functions compared with their cytoplasmic They can bind to actin monomers, actin polymers or both (2). counterparts in extensive activities of living cells. In addition Early studies have focused on the biological features and to the ability to regulate actin cytoskeleton dynamics, nuclear physiological mechanisms of cytoplasmic actin. Therefore, ABPs are associated with multiple nuclear biological processes, ABPs were considered to be distributed only in the cytoplasm including chromatin remodeling, gene transcriptional regula- and associated with the organization of actin cytoskeleton (3). tion, DNA damage response, nucleocytoplasmic trafficking In the cytoplasm, actin is associated with numerous cellular and nuclear structure maintenance. The nuclear translocation activities, including sustaining cellular morphology, deter- of ABPs is affected by numerous intracellular or extracellular mining cellular organelle distribution, mediating intracellular stimuli, which may lead to developmental malformation, transfer, endocytosis and exocytosis, cell division, cell migration tumor initiation, tumor progression and metastasis. Abnormal and adhesion (4-8). Meanwhile, ABPs regulate actin cytoskel- expression of certain ABPs have been reported in different etal structure by modulating actin filament cross‑linking into types of cancer. This review focuses on the newly identified networks or depolymerizing into monomers, allowing actin to roles of nuclear ABPs in the pathological processes associated switch between the polymeric (F‑actin form, filamentous actin) with cancer. and monomeric state (G-actin form, globular actin) (2,9). However, recent studies (10,11) indicate that a great number of actin and ABPs exist in the nucleus. Nuclear actin Contents and nuclear ABPs exhibit nuclear‑specific functions that are different from those in the cytoplasm. Although the precise 1. Introduction biological mechanisms remain elusive, we are fortunate to 2. Actin and actin-binding proteins (ABPs) in the nucleus uncover several observations (12). This review aims to present 3. Nuclear ABPs in cancer cells up-to-date discoveries of nuclear actin and nuclear ABPs in 4. Conclusion and perspectives the field of cancer research. 2. Actin and actin‑binding proteins (ABPs) in the nucleus 1. Introduction Studies in the recent decades provide a plethora of evidence Actin is one of the most abundant proteins identified in almost that has broadened our horizon on the functions of nuclear actin all eukaryotic cells, and it is a highly conserved protein during and nuclear ABPs in the eukaryotic cell life (12-14). Since the evolution (1). Actin-binding proteins (ABPs) refer to proteins existence of nuclear actin was confirmed, subsequent studies also established the presence of ABPs in the nucleus (12,14,15). The very first nuclear ABP was reported as early as 1987, hence- forth, the rest of the ABP family in the nucleus has come to light comprising of proflilin, anillin, flightless I (Fli I), filaminα Correspondence to: Dr Ying Lin, Department of Gastroenterology (FLNα), α-actinins, myosins, gelsolin and ezrin-radixin-moesin and Hepatology, Sun Yat-sen Memorial Hospital, Sun proteins (12,13,16,17). Although these ABPs are primarily in the Yat-sen University, 107 West Yanjiang Road, Guangzhou, Guangdong 510120, P.R. China cytoplasm, they can translocate into the nucleus under certain E-mail: [email protected] circumstances, for example, extracellular stimuli (stress), hormone stimulation and intracellular signaling (16). Key words: actin-binding protein, nuclear, actin, transcription, In the nucleus, actin is associated with chromatin remod- cancer eling, DNA replication, DNA repair, gene transcriptional regulation, RNA processing, nuclear protein transportation and maintenance of nuclear structure, for instance, the nuclear 2744 YANG and LIN: NUCLEAR ABPs IN HUMAN CANCER envelope assembly (12,18-20). Nuclear ABPs are closely associ- adenocarcinoma (33,34). Furthermore, villin is distributed in ated to nuclear actin and implicated in various nuclear activities. the cytoplasm and nucleus and cytoplamic-nuclear transport ABPs promote actin filament nucleation or sequestering, of villin keeps the system dynamically stable. It migrates to manipulate nuclear actin dynamics and determine the ratio of the nucleus upon stimulation, including hypoxia and injury. nuclear to cytoplasmic actin (13). Therefore, ABPs directly or Another postulation is that tyrosine phosphorylation of villin indirectly associate with chromatin remodeling, DNA replica- may prompt its gathering in the nucleus. A study reveals that tion, transcription, DNA repair, nucleocytoplasmic transport villin in the nucleus can interact with ZBRK1 [also called zinc and maintenance of nuclear structure integrity (12,13,21). finger and breast cancer type 1 (BRCA1)‑interaction protein], Furthermore, nuclear actin is required by all three RNA a transcriptional corepressor and also a ligand of the human polymerases in transcriptional activation (22-24). The study Slug promoter, thus regulating the activity of Slug and gene by Miyamoto and Gurdon (25) mentions the major function expression (34). of nuclear actin and ABPs in transcriptional regulation and The villin-ZBRK1 complex eliminates the corepressor nuclear reprogramming. effect of ZBRK1 and upregulates Slug expression. Slug is a In eukaryotic cells, the cytoplasm and nucleus are sepa- crucial transcriptional regulator of epithelial-mesenchymal rated by the nuclear envelope, which is a double membrane transition (EMT). Therefore, nuclear villin performs an barrier. Trafficking of proteins and other molecules between important role in inducing EMT, which is considered essential these two compartments occurs by passing through the nuclear in tumorigenesis (34), invasiveness and metastasis. A previous pore complex. Additionally, cytoplasmic ABPs can interact study demonstrates that severe combined immunodeficiency with the nuclear receptor in the cytoplasm, form complexes mice injected with xenografts derived from five colon cancer and facilitate nuclear translocation. Therefore, ABPs mediate cell lines developed tumors in 21 days at a 100% frequency, transcriptional activation of nuclear receptors. These nuclear and by staining with villin antibodies, the xenografts reveal receptors include the glucocorticoid and estrogen receptor, strong nuclear accumulation of villin (34). Furthermore, villin androgen receptor (AR), thyroid receptor and peroxisome expression is observed in gastric, colorectal, pancreatic, biliary, proliferator-activated receptor-c (26-28). Furthermore, they liver, renal, cervical, endometrioid, lung and other types of are associated with transcriptional activation of multiple genes cancer (34-36), particularly with propensity for metastasis and and are involved in a spectrum of functions, including cell poor prognosis. proliferation, differentiation and apoptosis (21,29,30). α-actinin 4 (ACTN4), a member of the ABP family, is a regulator of gene transcription that is presumably mediated 3. Nuclear ABPs in cancer cells by nuclear hormone receptors. Although the majority of ACTN4 is located in the cytoplasm, the proportion of ACTN4 Numerous ABPs demonstrate the ability to shuttle between in the nucleus is unneglectable. ACTN4 binds to the nuclear the cytoplasm and nucleus via different mechanisms. The receptors in a hormone-dependent manner. Furthermore, question remains whether it is the shuttling of ABPs between ACTN4 is a coactivator of the estrogen receptor α (ER-α) that different cellular compartments that is linked to pathological regulates target gene transcription in MCF-7 breast cancer behaviors, including abnormal cell development and differen- cells, subsequently promoting tumor cell proliferation (37). tiation, carcinogenesis and metastasis. However, this needs to Overexpression of ACTN4 in the nucleus increases the expres- be clarified. The theory that ABPs in the nucleus affect the sion of progesterone receptors and antigen related to ER (pS2), aforementioned pathological processes is intriguing. In the and target genes of ER-α (Fig. 1). Furthermore, it can interact sections, the nuclear ABPs that are associated with chromatin with the pS2 promoter and potentiate estradiol (E2)-induced remodeling, transcriptional regulation, DNA damage repair, transcription. Additionally, it interacts with the AR and func- protein nucleocytoplasmic shuttling and nuclear structure tions as a co-regulator of AR-mediated transcription (38). maintenance in human cancer cells are summarized in Table I Nuclear ACTN4 serves as a transcriptional coactivator and Fig. 1. for nuclear factor κ-light-chain enhancer of activated B-cell Fli I homolog (FLII), with a C-terminal gelsolin-like (NF-κB) (39). NF-κB activation in ERα-negative breast actin-binding domain, is a member of the gelsolin protein cancer promotes cancer cell proliferation (40). Furthermore, superfamily.