State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Cell Death Differ. 2020 Jun;27(6):1981-1997. doi: 10.1038/s41418-019-0475-6. Epub 2019 Dec 12.
Squamous cell carcinoma (SCC) is defined as a category of aggressive malignancies arising from the squamous epithelium of various organs. Resistance to chemotherapies is a common feature of SCCs, which leads to a poor prognosis among SCC patients. Recently, studies have illustrated the essential tumor suppressive role of ARID1A in several cancer types, but its role in SCCs remains unclear. Cancer stemness has been recognized as a main reason for tumorigenesis and is commonly correlated with chemoresistance, yet the relationship between ARID1A and cancer stemness remains unknown. In this study, we showed that Arid1a conditional knockout mice had a high incidence of SCCs occurring in the tongue and esophagus. ARID1A depletion promoted tumor initiation and cancer stemness in human SCC cells. Mechanistic studies revealed that ARID1A blocked the interaction between cyclin-dependent kinases (CDKs) and retinoblastoma protein (Rb), reducing the phosphorylation of Rb. Dephosphorylated Rb suppressed E2F1 activity and then suppressed cancer stemness by inactivating c-Myc. Furthermore, we showed that ARID1A depletion significantly increased the chemoresistance of SCC and that a CDK inhibitor exhibited a favorable effect on rescuing the chemoresistance caused by ARID1A loss. Collectively, our study showed that ARID1A inhibits the cancer stemness of SCCs by competing with CDKs to bind with Rb to inhibit the E2F1/c-Myc pathway.
鳞状细胞癌（SCC）被定义为一类源自各种器官鳞状上皮的侵袭性恶性肿瘤。对化疗的耐药性是 SCC 的一个共同特征，这导致 SCC 患者的预后较差。最近的研究表明，ARID1A 在几种癌症类型中具有重要的肿瘤抑制作用，但它在 SCC 中的作用尚不清楚。癌症干性已被认为是肿瘤发生的主要原因，并且通常与化疗耐药性相关，然而，ARID1A 与癌症干性之间的关系尚不清楚。在这项研究中，我们表明 Arid1a 条件性敲除小鼠在舌和食管中发生 SCC 的发生率很高。ARID1A 缺失促进了人 SCC 细胞的肿瘤起始和癌症干性。机制研究表明，ARID1A 阻断了细胞周期蛋白依赖性激酶（CDKs）和视网膜母细胞瘤蛋白（Rb）之间的相互作用，从而降低了 Rb 的磷酸化。去磷酸化的 Rb 抑制 E2F1 活性，然后通过失活 c-Myc 来抑制癌症干性。此外，我们表明 ARID1A 缺失显著增加了 SCC 的化疗耐药性，而 CDK 抑制剂对挽救 ARID1A 缺失引起的化疗耐药性具有良好的效果。总之，我们的研究表明，ARID1A 通过与 CDK 竞争与 Rb 结合来抑制 E2F1/c-Myc 通路，从而抑制 SCC 的癌症干性。
