多药耐药是卵巢癌患者在治疗过程中所面临的严重问题。尽管大部分患者在初始治疗时对于铂类及紫杉醇等药物比较敏感，但随着化疗药物的治疗过程进展，很多患者会出现获得性耐药的表型。多药耐药的产生将导致一线药物治疗无效以及最终导致患者的不良预后。ARID1A在近年来被认为是一个十分重要的抑癌基因，二代测序研究发现其在卵巢癌中的突变率极高，因此研究ARID1A在卵巢癌中的功能具有重要的临床价值。之前的研究提示ARID1A的表达与卵巢癌患者的化疗抵抗呈正相关，但是ARID1A在卵巢癌耐药中的具体作用尚不清楚，急需进一步的研究数据加以支撑。在本研究中，我们发现ARID1A的敲降能够显著抑制卵巢癌细胞的凋亡并导致其对卡铂及紫杉醇的多药耐药。另一方面，在ARID1A突变缺失的卵巢癌细胞系中外源过表达ARID1A能够促进卵巢癌细胞凋亡以及增加其对化疗药物的敏感性。进一步机制研究发现，ARID1A的缺失通过染色质重塑机制介导对多药耐药基因MRP2表达水平的调控，通过促进MRP2的表达而导致多药耐药的产生。除此之外，通过对150例卵巢癌标本进行免疫组织化学分析，我们发现ARID1A的表达水平与MRP2的表达水平呈显著负相关，验证了ARID1A对MRP2表达的负调控关系。更重要的是，ARID1A的表达水平与卵巢癌患者对铂类的敏感性呈正相关，而MRP2的表达水平与卵巢癌患者对铂类的敏感性呈负相关，这也与我们的功能实验结果相吻合。综上所述，我们的研究发现ARID1A的缺失可以通过转录激活MRP2从而导致卵巢癌的多药耐药。而靶向MRP2可能为逆转ARID1A缺失导致的卵巢癌多药耐药提供潜在的临床应用前景。

SWI/SNF染色质重塑复合物在人类肿瘤中突变率约20%，且ARID1A是SWI/SNF染色质重塑复合物中突变率最高的亚基。然而，包括ARID1A在内的一些SWI/SNF复合物的亚基在鳞状细胞癌中的突变率极低，并且它们在鳞状细胞癌中的作用尚不清楚。在这篇文章中，我们证实启动子区高甲基化是导致ARID1A在鳞状细胞癌中低表达的主要因素。ARID1A低表达与鳞状细胞癌患者的不良预后相关。分子机制方面，我们发现ARID1A通过直接以及间接的染色质重塑机制维持鳞状细胞癌细胞内转录组的稳态。而ARID1A的缺失通过激活促癌转录组进而促进鳞状细胞癌的进展。除此之外，我们还发现抗炎天然产物小白菊内酯 (parthenolide) 能够通过同时抑制HDAC1以及促癌通路从而对ARID1A缺失的鳞状细胞癌细胞具有协同致死的作用。根据这些发现，我们提出了将小白菊内酯应用于ARID1A低表达的鳞状细胞癌患者的临床应用前景。

鳞状细胞癌泛指起源于不同器官的鳞状上皮的一类进展性恶性肿瘤。对化疗药物的抵抗是鳞状细胞癌病例的常见特征，并往往因此导致不良预后。近年来，研究已经证实ARID1A在多种肿瘤类型中发挥重要的抑癌功能，但它在鳞状细胞癌中功能未知。肿瘤干细胞特性被认为是导致肿瘤发生的关键因素之一，并且也被认为与化疗抵抗密切相关，而目前ARID1A与肿瘤干细胞特性的关系尚不清楚。在本研究中，我们发现Arid1a条件敲除小鼠与野生型小鼠相比，舌与食管的鳞状细胞癌发生率明显增高。ARID1A 的敲降同样可以增加人鳞状细胞癌细胞的肿瘤发生及肿瘤干细胞特性。进一步机制研究发现，ARID1A可以阻碍周期依赖激酶 (CDKs) 与视网膜母细胞瘤蛋白 (Rb) 的结合，进而抑制Rb的磷酸化水平。Rb蛋白的去磷酸化抑制了E2F1的活性，并通过抑制c-Myc的表达来抑制肿瘤干细胞特性。除此之外，我们还发现ARID1A的敲降能够显著增加鳞状细胞癌的化疗抵抗能力，而CDK抑制剂对于逆转ARID1A缺失引起的化疗抵抗具有良好效果。综上所述，我们的研究揭示了ARID1A通过抑制CDKs与Rb结合进而抑制E2F1/c-Myc通路来抑制鳞状细胞癌的肿瘤干细胞特性。

鳞状细胞癌是一种进展性上皮恶性肿瘤，而目前其发病机制尚不完全清楚。ARID1A在多种癌种中突变频率较高，而其突变率在鳞状细胞癌中很低。然而，ARID1A在鳞状细胞癌中蛋白表达水平也比正常组织中低，这说明有其它非突变机制导致了ARID1A在鳞状细胞癌中的表达被抑制。本研究中，我们揭示了过度的泛素蛋白酶体途径降解是导致ARID1A在鳞状细胞癌中的低表达的机制之一。我们进一步明确E3泛素连接酶TRIM32以及去泛素化酶USP11在调控ARID1A的稳定性中发挥关键作用。敲降TRIM32通过稳定ARID1A从而抑制鳞状细胞癌细胞的增殖、转移、以及化疗抵抗；而敲降USP11通过促进ARID1A降解而促进鳞状细胞癌发展。除此之外，我们还发现syndecan-2 (SDC2) 是ARID1A与USP11的共同下游，并且证明了SDC2的敲降可以抵消ARID1A敲降所引起的促癌转化，说明SDC2是ARID1A在鳞状细胞癌中发挥抑癌功能的关键下游分子。综上所述，我们的研究揭示了泛素蛋白酶体介导的蛋白降解是ARID1A在鳞状细胞癌中失活的机制之一，并提出了TRIM32/USP11-ARID1A-SDC2调控轴在鳞状细胞癌发生发展中的重要作用。

Multiple Drug Resistance (MDR) of ovarian cancer is a severe trouble for ovarian cancer patients, which always contributes to treatment failure and bad prognosis. AT-rich interaction domain 1 A (ARID1A) has been recognized as a bona fide tumor suppressor gene in recent years, with a very high mutation rate in ovarian cancer. Previous study indicated that ARID1A expression is negatively correlated with chemoresistance of ovarian cancer patients. However, the specific role of ARID1A in chemoresistance of ovarian cancer remains elusive. In this study, we showed that ARID1A depletion in ovarian cancer cells significantly reduced their apoptosis rate and led to MDR, while ectopic expression of ARID1A promotes cell apoptosis and chemosensitivity of ovarian cancer cells. Mechanistic studies revealed that ARID1A depletion transcriptionally activates the expression of multidrug resistance-associated protein 2 (MRP2) via chromatin remodeling. IHC analysis of 150 ovarian cancer samples confirmed that ARID1A expression was strong negatively correlated with MRP2 expression. More importantly, both ARID1A and MRP2 expression levels are correlated with sensitivity to platinum. Collectively, our results illustrate that ARID1A loss in ovarian cancer leads to MDR through upregulation of MRP2, and provide an opportunity to overcome the ARID1A loss induced chemoresistance of ovarian cancer by targeting MRP2.

Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have a mutation rate of ~20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat SCC patients with low ARID1A expression.

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.

Squamous cell carcinoma (SCC) is an aggressive epithelial malignancy, yet the molecular mechanisms underlying SCC development are elusive. ARID1A is frequently mutated in various cancer types, but both the mutation rates and expression levels of ARID1A are ubiquitously low in SCCs. Here, we reveal that excessive ubiquitin-proteasome system (UPS)-mediated protein degradation contributes to the loss of ARID1A expression in SCC. We further identify the E3 ligase TRIM32 and the deubiquitinase USP11 play key roles in controlling ARID1A stability. TRIM32 depletion inhibits SCC cell proliferation, metastasis and chemoresistance by stabilizing ARID1A, while USP11 depletion promotes SCC development by promoting ARID1A degradation. We show that syndecan-2 (SDC2) is the downstream target of both ARID1A and USP11, and SDC2 depletion abolishes the oncogenic function of ARID1A loss. In summary, our data reveal UPS-mediated protein degradation as a mechanism underlying ARID1A loss and propose an important role for the TRIM32/USP11-ARID1A-SDC2 axis in SCC.