Kang Mo K, Chen Wei, Park No-Hee
The Shapiro Family Laboratory of Viral Oncology and Aging Research; Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry.
The Shapiro Family Laboratory of Viral Oncology and Aging Research; Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry; David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Crit Rev Oncog. 2018;23(3-4):201-217. doi: 10.1615/CritRevOncog.2018027608.
Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis.
颗粒头样蛋白2（GRHL2）最初被描述为与果蝇中决定果蝇表皮形成的颗粒头（GRH）具有序列同源性的三种哺乳动物异构体之一。早期研究将GRHL2表征为一种调节上皮形态发生和分化的上皮特异性转录因子。通过高通量蛋白质组学方法，我们发现GRHL2是人类端粒酶催化亚基编码基因hTERT的一种新型反式调节因子。在人类口腔鳞状细胞癌（OSCC）和原代正常人角质形成细胞中，GRHL2被发现对hTERT表达和端粒酶活性是必需且充分的。随后，我们发现了GRHL2的许多其他直接转录靶点，包括p63、微小RNA（miR）-200家族基因、FoxM1和表皮分化复合体（EDC）基因。这些靶分子介导了GRHL2对上皮细胞增殖、分化和上皮可塑性的表型效应。尽管其他一些研究也表明GRHL2具有肿瘤抑制作用，但GRHL2在OSCC细胞和组织中的异常过表达暗示了其促癌作用。利用新型的Grhl2条件性敲除（cKO）模型，我们最近报道了第一项基因研究，其中Grhl2敲除完全消除了由强效致癌物4-硝基喹啉N-氧化物（NQO）诱导的口腔致癌作用。在这篇综述中，我们讨论了GRHL2对上皮细胞增殖和分化的表型效应背后的机制见解，以及GRHL2可能促进口腔致癌的潜在机制。
