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Review Article Grainyhead-Like 2 As a Double-Edged Sword in Development and Cancer

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Review Article Grainyhead-Like 2 As a Double-Edged Sword in Development and Cancer Am J Transl Res 2020;12(2):310-331 www.ajtr.org /ISSN:1943-8141/AJTR0102841 Review Article Grainyhead-like 2 as a double-edged sword in development and cancer Jiaxing He1, Chunyang Feng1, He Zhu1, Shuying Wu1, Peng Jin2, Tianmin Xu1 1Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin, China; 2Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA Received September 26, 2019; Accepted January 4, 2020; Epub February 15, 2020; Published February 28, 2020 Abstract: Grainyhead-like 2 (GRHL2), one of the three homologs of Drosophila grainyhead, contributes to epithe- lial morphogenesis and differentiation. Dysregulation of GRHL2 has been shown to be involved in hearing loss and neural tube defects during embryogenesis. Moreover, it is well-recognized that GRHL2 suppresses epithelial- to-mesenchymal transition (EMT) that is required for migration and invasion of carcinoma, implicating, GRHL2 in carcinogenesis. Diverse mechanisms, as well as the varied roles of GRHL2 in different tumor tissues, have been elucidated. However, the functions of GRHL2 appear to be more complicated than initially thought. GRHL2, acting as either a tumor enhancer or a tumor inhibitor, depends on the type of cancer. In this review, we summarize research progress about normal physiological functions of GRHL2 including epithelial morphogenesis, neural tube closure, and hearing loss. Moreover, the mechanisms of GRHL2 in tumorigenesis, containing EMT suppression, forming a negative feedback loop with ZEB1 and miR200 family, interactions with estrogen receptor (ER)-dependent signal- ing pathway, regulation of telomerase reverse transcriptase and relationships with TGF-beta signaling pathway are discussed in this review in an effort to better understand the roles of GRHL2 in a variety of cancers toward the goal of GRHL2-targeted treatment in the near future. Keywords: Grainyhead-like 2, epithelial morphogenesis, neural tube closure, tumorigenesis, epithelial-to-mesen- chymal, estrogen receptor Introduction the cellular processes including cell cycle pro- gression and cell survival are observed as well The Grainyhead (GRH) gene, the first member [7-9]. The LSF subfamily is systematically of the Grainyhead-like (GRHL) proteins family, reviewed in the context of cancer [10]. Unlike was first reported in mutant Drosophila mela- LSF, GRHL proteins, a highly-conserved sub- nogaster embryos that showed a head defect: family, are associated with the development holes in large specific cuticular regions, abnor- and maintenance of the epithelial barrier. mal lack of cuticular structures leading to a During murine development, GRHL proteins are specific phenotype [1]. Later, more GRH family expressed in the epidermis, oral cavity, gastro- members and their specific functions were dis- intestinal tract and non-ectoderm-derived tis- covered [2-4]. According to differences of their sues including the heart, the lung and the kid- biological roles, these family members are split ney [11]. Roles of GRHL proteins have been into two different subfamilies, the LSF subfam- widely studied in the normal and abnormal ily including CP2, LBP-1a, and LBP-9 transcrip- development of the epidermis. GRHL1-null mice tion factors and the GRH subfamily, consisting show defective hair anchoring, altered keratino- of GRHL1, GRHL2, and GRHL3 transcription cyte terminal differentiation and abnormal des- factors [5, 6]. The biological roles of the LSF mosomes suggesting that GRHL1 may play a subfamily are distinguished from those of GRH key role in maturation and differentiation of epi- subfamily in that they widely regulate tissue dermis [12]. It has also been shown that the development such as liver function and neural loss of GRHL1 has an essential influence on the system development. Additionally, regulation of maintenance of the epidermal barrier [13]. The Role of GRHL2 in development and cancer GRHL3 protein is necessary for neural tube clo- transition, miR200 family as well as human sure and wound healing, knockdown of GRHL3 telomerase reverse transcriptase. Furthermo- results in spina bifida and severe barrier de- re, the role of GRHL2 appears to be more com- fects with death at birth [11, 14-16], relevant plicated than we predicted. In the present mechanisms are also explored and studied [17, review, we summarize research progress ab- 18]. out the normal physiological functions of GR- HL2 including epithelial morphogenesis, neural GRHL transcription factors are classified as tube closure, and hearing loss. Moreover, the DNA-binding nuclear proteins containing a tr- mechanisms of GRHL2 in tumorigenesis, con- ansactivation domain, a highly conserved DNA- taining EMT suppression, forming a negative binding domain (DBD), and a dimerization do- feedback loop with ZEB1 and miR200 family, main. The GRHL DBD is more structured than interactions with ER-dependent signaling path- the transactivation domains. Despite their way, regulation of telomerase reverse transcrip- importance in development and tumorigenesis, tase and relationships with the TGF-beta signal- their structure and DBD remain elusive. The ing pathway are discussed in an effort to better crystallographic analysis shows that GRHL1 understand the roles of GRHL2 in a variety of and GRHL2 share a highly conserved three- cancers toward the goal of GRHL2-targeted dimensional structure characterized by an IgG- treatment in the near future. like core. A recent report presents the first crys- tal structures study of mammalian GRHL1 DBD Physiological functions of GRHL2 in mammals and GRHL2 DBD. Their structures are closely similar and contain an Ig-like core decorated by A study by Riethdorf et al [21] revealed the ex- pression relevance of GRHL2 in a variety of nor- three α helices and a series of surface loops. mal tissues by performing a comprehensive The crystal structure of the GRHL1 DBD sh- immunohistochemical analysis. Many studies ows consensus binding sequence (AACCGGTT) show the irreplaceable role of GRHL2 in neural which is shared by all members of the GRHL tube closure during embryogenesis as well as family bound to a 12-base-pair DNA duplex. regulation of epithelial phenotype. Moreover, Lys386 benefits the overall stabilization of the hearing loss is partially regulated by GRHL2. DBD-DNA complex. Arg427, Gly387, and Arg- Thus GRHL2 may serve as an important tran- 430 are required for formation of DBD-DNA scription factor for embryo development and complex [19]. Interestingly, the protein fold of maintenance of tissues. the GRHL1 DBD resembles the tumor suppres- sor p53 and their DNA-binding modes are simi- GRHL2 influences neural development and lar suggesting cooperation of p53 and GRHL formation of the craniofacial skeleton during proteins during epidermal development and embryogenesis function [19, 20]. Neural tube closure is necessary for the devel- Recently, GRHL2 has drawn great attention for opment of the central nervous system (CNS) its physiological functions in embryogenesis during embryogenesis. If neural tube closure is and diseases including cancer. The GRHL2 defective, it will lead to neural tube defects gene is located on human chromosome 8q22. (NTDs). As the most common birth defect in GRHL2 expression is detected in epidermis tis- humans, NTDs result in malformations of the sue, lung and kidney during murine embryogen- face and brain. The most common NTDs are esis. Placenta, brain, lung, salivary gland, thy- anencephaly arising from defective closure of mus, and pancreas in human adults show rela- anterior neural tube closure, and spina bifida tive high GRHL2 expression. Therefore, once resulting from the failure of neural tube closure GRHL2 is in a disorder condition, disease may in the spinal column [22]. To date, more than follow. To date, many studies have emphasized 200 underlying genes have been associated the mechanisms and roles of GRHL2 in diseas- with NTDs [23, 24]. It has been shown that the es. It is well established that GRHL2 regulates Grainyhead family, including both GRHL2 and epithelial morphogenesis, neural tube closure, GRHL3, is involved with NTDs. The upregulation and hearing loss. In addition, GRHL2 contrib- of GRHL2 is observed in mutant NTDs murine utes to the tumorigenesis via various signaling embryos [25]. Discussed here, and summa- pathways such as epithelial-to-mesenchymal rized in Figure 1, GRHL2 deletion mice exhibit 311 Am J Transl Res 2020;12(2):310-331 Role of GRHL2 in development and cancer epithelial character in surface ectoderm, ectopic expression of N-cadherin and Sox2 indi- cates the gain of neuroepithe- lial characteristics. Mechani- stically, loss of epithelial char- acteristics in GRHL2 null em- bryos is associated with ac- tomyosin disorganization, cell shape and thickness, and ch- ange in the balance of cell-cell junctional strength in the sur- face ectoderm layer. GRHL2 overexpression embryos most likely regulate the composition of apical junction complexes and increased cell-cell stress via the actomyosin network altering the biomechanical pr- operties in the surface ecto- derm [28]. GRHL2 acts as a suppressor Figure 1. GRHL2 influences neural development and formation of the cra- of EMT and promotes neural niofacial skeleton during embryogenesis. GRHL2 dysregulation may exhibit tube closure [29]. Epithelial severe defects during development such as anencephaly, spina bifida, split- splicing regulatory protein 1 face malformation, ventricle formation and otic vesicle defects, MHB
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