Banerjee Rajat, Russo Nickole, Liu Min, Van Tubergen Elizabeth, D'Silva Nisha J
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Small GTPases. 2012 Jul-Sep;3(3):192-7. doi: 10.4161/sgtp.20413. Epub 2012 Jun 11.
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, globally. Previously, we showed that Rap1GAP is a tumor suppressor gene that inhibits tumor growth, but promotes invasion in SCCHN. In this work, we discuss the role of Rap1 and Rap1GAP in SCCHN progression in the context of a microRNA-oncogene-tumor suppressor gene axis, and investigate the role of Rap1GAP in EZH2-mediated invasion. Loss of expression of microRNA-101 in SCCHN leads to upregulation of EZH2, a histone methyltransferase. Overexpression of EZH2 silences Rap1GAP via methylation, thereby promoting activation of its target, Rap1. This microRNA-controlled activation of Rap1, via EZH2-mediated silencing of Rap1GAP, is a novel mechanism of Rap1 regulation. In two independent SCCHN cell lines, downregulation of EZH2 inhibits proliferation and invasion. In both cell lines, stable knockdown of EZH2 (shEZH2) recovers Rap1GAP expression and inhibits proliferation. However, siRNA-mediated knockdown of Rap1GAP in these cells rescues proliferation but not invasion. Thus, EZH2 promotes proliferation and invasion via Rap1GAP-dependent and -independent mechanisms, respectively. Although the studies presented here are in the context of SCCHN, our results may have broader implications, given that Rap1GAP acts as a tumor suppressor in pancreatic cancer, thyroid cancer, and melanoma.
头颈部鳞状细胞癌（SCCHN）是全球第六大常见癌症。此前，我们发现Rap1GAP是一种肿瘤抑制基因，可抑制肿瘤生长，但会促进头颈部鳞状细胞癌的侵袭。在这项研究中，我们在微小RNA-原癌基因-肿瘤抑制基因轴的背景下讨论了Rap1和Rap1GAP在头颈部鳞状细胞癌进展中的作用，并研究了Rap1GAP在EZH2介导的侵袭中的作用。头颈部鳞状细胞癌中微小RNA-101表达缺失导致组蛋白甲基转移酶EZH2上调。EZH2过表达通过甲基化使Rap1GAP沉默，从而促进其靶点Rap1的激活。这种通过EZH2介导的Rap1GAP沉默而由微小RNA控制的Rap1激活是Rap1调控的一种新机制。在两个独立的头颈部鳞状细胞癌细胞系中，EZH2下调会抑制增殖和侵袭。在这两个细胞系中，EZH2的稳定敲低（shEZH2）可恢复Rap1GAP表达并抑制增殖。然而，这些细胞中siRNA介导的Rap1GAP敲低可挽救增殖但不能抑制侵袭。因此，EZH2分别通过Rap1GAP依赖和非依赖机制促进增殖和侵袭。尽管此处介绍的研究是在头颈部鳞状细胞癌的背景下进行的，但鉴于Rap1GAP在胰腺癌、甲状腺癌和黑色素瘤中作为肿瘤抑制因子发挥作用，我们的结果可能具有更广泛的意义。
