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Abstract

Grainyhead-like 2 is a human homolog of Drosophila grainyhead. It inhibits epithelial-to-mesenchymal transition that is necessary for cell migration, and it is involved in neural tube closure, epithelial morphogenesis, and barrier formation during embryogenesis by regulation of the expression of cell junction proteins such as E-cadherin and vimentin. Cancer shares many common characters with development such as epithelial-to-mesenchymal transition. In addition to its important role in development, grainyhead-like 2 is implicated in carcinogenesis as well. However, the reports on grainyhead-like 2 in various cancers are controversial. Grainyhead-like 2 can act as either a tumor suppressor or an oncogene with the mechanisms not well elucidated. In this review, we summarized recent progress on grainyhead-like 2 in development and cancer in order to get an insight into the regulation network of grainyhead-like 2 and understand the roles of grainyhead-like 2 in various cancers.

Keywords

E-cadherin epithelial-to-mesenchymal transition metastasis oncogene tumor suppressor

Introduction

Grainyhead is a transcription factor that is necessary for the correct morphology and characteristic of epithelial tissues during Drosophila embryogenesis.^1–3 It is also known as Brother-of-Mammalian grainyhead (BOM)⁴ and transcription factor cellular promoter 2-like 3 (TFCP2L3).⁵ Disruption of the gene function is embryonic lethal.³ This protein family of transcription factors is conserved from fly to human. Grainyhead-like 1 (GRHL1), grainyhead-like 2 (GRHL2), and grainyhead-like 3 (GRHL3) are identified as homologs of grainyhead in human.^4,6,7

The gene for GRHL2 is mapped to human chromosome 8q22.⁵ GRHL2 expression can be detected in skin, lung, esophagus, and kidney during murine embryogenesis. In human adults, GRHL2 is expressed in placenta, brain, kidney, prostate, thymus, lung, salivary gland, mammary gland, digestive tract, and pancreas.^4,5

Three isoforms of GRHL2 have been identified so far. Isoform 1 represents the full length of GRHL2; the translation of isoform 2 starts at an alternative site which results in a protein that is five amino acids shorter than isoform 1 in addition to six amino acids substitution at N-terminal. Compared with isoform 1, isoform 3 lacks 98 amino acids at N-terminal resulting in the loss of transcription activity. All three isoforms are expressed in pancreas and brain. In addition, isoform 1 is detected in testis, prostate, placenta, colon, kidney, and lymph node, while isoform 2 is detected in tonsil, thymus, placenta, and kidney, and isoform 3 is detected in testis.⁷

Studies in Drosophila indicated that the grainyhead proteins can form dimers through its c-terminal and the dimer can stabilize its interaction with DNA. The DNA binding domain localizes in the middle of grainyhead, and the domain with transcription activity is close to the N-terminal.^7–9 The alignment of GRHL2 with grainyhead suggests similar distribution of the three function domains in GRHL2⁷ (Figure 1).

Figure 1.

Schematic structure of human GRHL2 and Drosophila grainyhead.

GRHL2 is necessary for neural tube closure during embryogenesis

Neural tube closure is a crucial step in the development of central nervous system during embryogenesis. The closure starts at the caudal hindbrain/rostral spinal cord and continues through the head and goes down along the spinal cord. Failure of neural tube closure leads to neural tube defects¹⁰ which is one of the most common serious birth defects.

The non-neural ectoderm is crucial for full neural tube closure.^11,12 It can influence the patterning of the dorsal neural tube¹³ and induces neural crest cells.¹⁴ GRHL2 is expressed in the non-neural ectoderm. It promotes the expression of key epithelial genes and suppresses epithelial-to-mesenchymal transition (EMT) to keep the epithelial nature of the non-neural ectoderm during the formation of neural tube. Mutation of GRHL2 leads to the loss of non-neural ectoderm integrity and abnormal mesenchymal phenotype in non-neural ectoderm by downregulation of EMT suppressors Esrp1, Sostdc1, Fermt1, Tmprss2, and Lamc2.¹⁵ In addition, loss of GRHL2 function inhibits the expression of E-Cadherin¹⁶ that is important to keep the epithelial phenotype of cells and enhances vimentin expression, leading to impaired cellular dynamics that affects the non-neural ectoderm and neural crest cells.¹⁵ Knockout of GRHL2 is embryonic lethal and the embryos die at E11.5. In the GRHL2 knockout murine embryos, the posterior neuropore keeps open and a fully penetrant split-face malformation and cranioschisis is observed.¹⁷

Expression of GRHL2 during neural tube closure is regulated by tet methylcytosine dioxygenase 1 (TET1).¹⁸ TET1 catalyzes the conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) and regulates gene expression.¹⁹ Mutation of TET1 leads to enzyme activity loss in tuft embryo heads which results in reduced expression of multiple genes including GRHL2 that are associated with neural tube closure.¹⁸

GRHL2 regulates junction formation of epithelial cells

The formation of an apical junctional complex including adherens junctions and tight junctions is necessary for the definition of cell polarity, junction formation, and differentiation of epithelial cells during embryogenesis. The regulation of junction formation by GRHL2 is widely studied in various epithelial cells in addition to its necessary role in neural tube closure.

GRHL2 can activate the transcription and regulate the expression of the adherens junction gene E-cadherin and the tight junction genes claudin 3 (Cldn3) and claudin 4 (Cldn4) in several types of epithelia, and it is crucial for epithelial differentiation.²⁰ GRHL2 also upregulates Rab25 that enhances the localization of Cldn4 in the tight junction.²¹

GRHL2 is involved in the regeneration of a polarized mucociliary epithelium from basal stem cells in pseudostratified airway epithelium of the lung. It upregulates the expression of both notch and ciliogenesis genes (Mcidas, Rfx2, and Myb), and promotes organoid morphogenesis and the differentiation of ciliated cells.²² Furthermore, GRHL2 is the key regulator of cell morphogenesis, adhesion, and motility of human airway epithelium in adults.²³ GRHL2 and NK2-homeobox 1 transcription factor (Nkx2-1) can enhance the expression of each other and they form a positive feedback loop in lung epithelial cells. Downregulation of GRHL2 and Nkx2-1 results in morphological changes of flattening lung alveolar type II cells. GRHL2 upregulates the expression of semaphorins and their receptors in addition to E-Cadherin and Cldn4, these genes contribute to impaired collective cell migration induced by GRHL2 mutation.²⁴

Expression of GRHL2 is high in chorionic trophoblast cells of placenta. Loss of GRHL2 leads to deficiency of basal chorionic trophoblast cell polarity, basement membrane integrity at the chorioallantoic interface, and labyrinth branching morphogenesis. GRHL2 can activate the transcription of genes that regulate placental development and epithelial morphogenesis, including serine peptidase inhibitor Kunitz type 1 (Spint1) that mediates basal chorionic trophoblast (BCT) cell integrity and labyrinth formation.²⁵

Kidney is another organ that has high expression of GRHL2. High expression of GRHL2 is detected in nephric duct, ureteric bud, and collecting duct epithelia in kidney. Loss of GRHL2 function results in deficient nephric duct lumen expansion and impaired epithelial barrier formation and inhibited lumen expansion in collecting duct epithelia in mice. GRHL2 activates the expression of the ovo-like 2 zinc finger transcription factor (Ovol2), which controls Cldn4 and Rab25 expression. The two genes promote lumen expansion and barrier formation in subtypes of epithelia in kidney.²⁶

In keratinocytes, GRHL2 directly binds to the promotor of p63 and promotes expression of p63. The p63 keeps the epithelial phenotype and inhibits the EMT of keratinocytes.²⁷ Expression of GRHL2 is inhibited by miR-217 in keratinocytes, and miR-217 promotes the differentiation of keratinocytes by downregulating GRHL2.²⁸ Germline GRHL2 mutation leads to autosomal-recessive ectodermal dysplasia syndrome characterized by nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. The mutation alters cell morphology and attenuates tight junctions, and induces adhesion defects and cytoplasmic translocation of GRHL2 from nucleus in keratinocytes.²⁹

GRHL2 in hearing loss

Correlation between GRHL2 and hearing loss was also studied. Mutations in GRHL2 can cause progressive autosomal dominant hearing loss,⁵ and that can be recapitulated in zebrafish carrying GRHL2B (homolog of human GRHL2 in zebrafish) mutation.³⁰ Single nucleotide polymorphisms of GRHL2 are associated with noise-induced hearing loss^31,32 and age-related hearing loss;³³ however, another study showed no correlation between single nucleotide polymorphisms of GRHL2 and age-related hearing loss.³⁴ The association between single nucleotide polymorphisms of GRHL2 and noise-induced hearing loss needs to be further confirmed.

GRHL2 inhibits metastasis of cancer

EMT is a process that epithelial cells lose cell–cell adhesion and cell polarity, and gain migratory and invasive abilities. During embryogenesis, cells such as neural crest cells undergo EMT and migrate to various sites and contribute to the formation of various organs. EMT occurs under pathological situations as well; cancer cells migrate from their primary sites and colonize at other sites after EMT, leading to the recurrence and treatment failure.³⁵ Due to its regulation on cell junction proteins and EMT in development, the role of GRHL2 in cancer metastasis was studied.

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that can downregulate or upregulate the expression of its target genes by recruiting co-suppressors or co-activators.^36,37 ZEB1 promotes EMT and cancer metastasis by inhibiting the expression of E-Cadherin that is important to keep cell adhesion.^38,39 High expression of ZEB1 is associated with low expression of E-Cadherin and advanced diseases of many tumors.^40
–43 GRHL2 can suppress EMT by inhibition of ZEB1 expression via direct repression of the ZEB1 promoter or by impairment of the Six1 and DNA complex in breast cancer. Overexpression of GRHL2 induces mesenchymal-to-epithelial transition (MET) of breast cancer cells.^44,45 GRHL2 expression is lost in the invasive front of primary tumors of breast cancer, and the loss of GRHL2 expression is associated with lymph node metastasis of breast cancer.⁴⁶ Loss of GRHL2 expression promotes the migration of epithelial ovarian cancer cells, and it correlates with the mesenchymal molecular subtype and a poor overall survival of epithelial ovarian cancer patients. GRHL2 directly activates the transcription of microRNA-200b/a which regulates the epithelial status of epithelial ovarian cancer through inhibition of the expression of ZEB1 and E-cadherin.⁴⁷ ZEB1 can inhibit expression of GRHL2 as well;⁴⁵ GRHL2 and ZEB1 form a negative feedback loop.

Partial EMT leads to a hybrid of epithelial/mesenchymal cells which migrate collectively during gastrulation and wound healing. In addition to the direct regulation on EMT, GRHL2 can stabilize hybrid epithelial/mesenchymal phenotype of lung cancer cells which is associated with aggressive tumor progression.⁴⁸

Transforming growth factor-β (TGF-β) is a cytokine that can act as both oncogene and tumor suppressor. It inhibits tumor growth by inducing cell cycle arrest and it induces EMT to promote tumor metastasis.^49,50 TGF-β mediated EMT can be suppressed by GRHL2 by inhibition of Smad2/3 activation, downregulation of ZEB1 expression, and upregulation of mir-200b/c and bone morphogenetic protein 2 (BMP2) expression.⁴⁴ GRHL2 expression is regulated by TGF-β as well. TGF-β and Wnt can downregulate GRHL2 expression through ZEB1.⁴⁵

GRHL2 enhances carcinogenesis

As a tumor suppressor, GRHL2 can inhibit EMT and cancer metastasis, and it is downregulated in many cancers. However, many studies showed that GRHL2 acts as an oncogene and it can enhance the proliferation of tumor cells. Overexpression of GRHL2 has been observed in several cancers such as oral squamous cell carcinoma,⁵¹ colorectal cancer,^52,53 and hepatocellular carcinoma.⁵⁴ High expression of GRHL2 enhances proliferation of cancer cells, leading to bad prognosis.

The mechanism that GRHL2 promotes cell proliferation has been studied. Knockdown of GRHL2 in oral squamous cell carcinoma cells results in reduced expression of human telomerase reverse transcriptase (hTERT), telomerase activity, and cell survival.⁵⁵ GRHL2 can inhibit the DNA methylation at the 5′-CpG Island in normal keratinocytes, resulting in the increase of hTERT expression and enhanced cell proliferation.⁵⁶ This finding proves the important role of hTERT in the regulation of GRHL2-mediated cell proliferation. Furthermore, GRHL2 suppresses death-receptor fas cell surface death receptor (FAS) expression and FAS induced apoptosis of cancer cells,⁵⁷ and it can promote the proliferation of cancer cells by upregulation of other oncogenes such as erb-b2 receptor tyrosine kinase 3 (ERBB3).⁴⁶

GRHL2 regulates the expression of cell junction proteins and inhibits EMT and metastasis of cancer cells when it acts as a tumor suppressor. It still shows the inhibitory role in EMT in oral squamous cell carcinoma and breast cancer when it acts as an oncogene that can enhance cancer cell proliferation and survival,^51,58 suggesting that the inhibition of EMT by GRHL2 and its contribution to cell proliferation might go through two independent pathways. Further studies are necessary to demonstrate the interaction between the regulation of EMT and cell proliferation by GRHL2 in order to well understand the opposite roles of GRHL2 in different cancers. The regulation network of GRHL2 is summarized in Figure 2.

Figure 2.

The regulation network of GRHL2.

Molecules that are upstream or downstream of GRHL2 in various cells are summarized together: red color, the molecule is an antagonist of EMT; blue color, the molecule is an agonist of EMT; green color, the molecule enhances cell proliferation; purple color, the molecule is related to cell survival.

Conclusion

GRHL2 is a key transcription factor in development. By regulation on the expression of cell junction proteins and inhibition of EMT, GRHL2 plays a crucial role in neural tube closure and epithelial cell morphology. In line to its inhibitory role in EMT in development, GRHL2 can inhibit EMT of cancer cells and cancer metastasis as well, and it is considered as a tumor suppressor in this context. However, GRHL2 can also act as an oncogene by promoting cell proliferation and survival. In agreement with the opposite roles of GRHL2 in various cancers, the expression of GRHL2 can be upregulated or downregulated in various tumors compared with normal tissues.⁵⁹ The controversial roles of GRHL2 in different cancers could be explained by the different cellular context of host cells. It is possible that the cellular context of host cells decides the availability of the signaling pathways that regulate EMT and cell proliferation by GRHL2, making GRHL2 behave as tumor suppressor or oncogene in different cancers. As an oncogene, GRHL2 could be a potential treatment target by inhibition of its activity. However, the tumor suppressing function of GRHL2 in certain types of cancers makes it complicated to target GRHL2 in cancer. GRHL2 is not widely studied in cancer so far, more studies are needed to well elucidate the role of GRHL2 in cancer and the knowledge could contribute to a better therapy of cancer.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work is supported by Ningxia Medical University Foundation (No. XZ2016001), Ningxia High Education Scientific Research Program (No. NGY2016120), National Natural Science Foundation of China (No. 81472770), and Science and Technology Commision of Shanghai Changning District (No. CNKW 2014102).

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Grainyhead-like 2 in development and cancer

Abstract

Keywords

Introduction

GRHL2 is necessary for neural tube closure during embryogenesis

GRHL2 regulates junction formation of epithelial cells

GRHL2 in hearing loss

GRHL2 inhibits metastasis of cancer

GRHL2 enhances carcinogenesis

Conclusion

Footnotes

Declaration of conflicting interests

Funding

References