ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness
ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness
复制标题
DOI：
10.1038/s41418-019-0475-6
复制
发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Liu, Zhihua
中科院分区：
文献类型：
--
作者：
Luo, Qingyu;Wu, Xiaowei;Liu, Zhihua
鳞状细胞癌（SCC）是一类发生于各种器官鳞状上皮的侵袭性恶性肿瘤。对化疗的抵抗是SCC的共同特征，这导致SCC患者的预后不良。最近，研究已经说明了ARID1A在几种癌症类型中的基本肿瘤抑制作用，但其在SCC中的作用仍不清楚。癌症的干性是肿瘤发生的主要原因，通常与化疗耐药性相关，但ARID1A与癌症干性之间的关系仍不清楚。在这项研究中，我们发现Arid1a条件性敲除小鼠在舌头和食管中发生SCC的发生率很高。ARID1A耗竭促进人SCC细胞中的肿瘤起始和癌症干细胞性。机制研究表明，ARID1A阻断细胞周期蛋白依赖性激酶（CDK）和视网膜母细胞瘤蛋白（Rb）之间的相互作用，减少Rb的磷酸化。去磷酸化Rb抑制E2F1活性，然后通过失活c-Myc抑制癌症的干性。此外，我们发现ARID1A缺失显著增加了SCC的化学抗性，并且CDK抑制剂对挽救由ARID1A缺失引起的化学抗性表现出有利的作用。总的来说，我们的研究表明，ARID1A通过与CDK竞争与Rb结合以抑制E2F1/c-Myc途径来抑制SCC的癌症干性。
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.