SOX2 is highly expressed and controls tumor initiation and cancer stem cell function in various squamous cell carcinomas including esophageal squamous cancer. However, the molecular mechanism leading to SOX2 overexpression in cancer is incompletely understood. Here, we identified CHIP, a chaperone-associated ubiquitin E3 ligase, as a novel negative regulator of SOX2 protein stability and tumorigenic activity in esophageal squamous carcinoma cells. We showed that CHIP interacted with SOX2 primarily via chaperone HSP70, together they catalyzed SOX2 ubiquitination and degradation via proteasome. In contrast, HSP90 promoted SOX2 stability and inhibition of HSP90 activity induced SOX2 ubiquitination and degradation. Notably, unlike the case in normal esophageal tissues where CHIP was detected in both the cytoplasm and nucleus, CHIP in clinical esophageal tumor specimens was predominantly localized in the cytoplasm. Consistent with this observation, we observed increased expression of exportin-1/CRM-1 in clinical esophageal tumor specimens. We further demonstrated that CHIP catalyzed SOX2 ubiquitination and degradation primarily in the nuclear compartment. Taken together, our study has identified CHIP as a key suppressor of SOX2 protein stability and tumorigenic activity and revealed CHIP nuclear exclusion as a potential mechanism for aberrant SOX2 overexpression in esophageal cancer. Our study also suggests HSP90 inhibitors as potential therapeutic agents for SOX2-positive cancers.

SOX2 在包括食管鳞癌在内的各种鳞状细胞癌中高表达并控制肿瘤发生和癌症干细胞功能。然而，导致癌症中 SOX2 过度表达的分子机制尚不完全清楚。在这里，我们确定了 CHIP（一种分子伴侣相关的泛素 E3 连接酶）作为食管鳞癌细胞中 SOX2 蛋白稳定性和致瘤活性的新型负调节因子。我们发现 CHIP 主要通过分子伴侣 HSP70 与 SOX2 相互作用，它们一起通过蛋白酶体催化 SOX2 泛素化和降解。相反，HSP90 促进 SOX2 稳定性，抑制 HSP90 活性会诱导 SOX2 泛素化和降解。值得注意的是，与在正常食管组织的细胞质和细胞核中均检测到 CHIP 的情况不同，临床食管肿瘤标本中的 CHIP 主要位于细胞质中。与这一观察结果一致，我们观察到临床食管肿瘤标本中导出蛋白-1/CRM-1 的表达增加。我们进一步证明 CHIP 主要在核区室中催化 SOX2 泛素化和降解。综上所述，我们的研究已确定 CHIP 是 SOX2 蛋白稳定性和致瘤活性的关键抑制因子，并揭示 CHIP 核排斥是食管癌中异常 SOX2 过表达的潜在机制。我们的研究还表明 HSP90 抑制剂可作为 SOX2 阳性癌症的潜在治疗药物。我们进一步证明 CHIP 主要在核区室中催化 SOX2 泛素化和降解。综上所述，我们的研究已确定 CHIP 是 SOX2 蛋白稳定性和致瘤活性的关键抑制因子，并揭示 CHIP 核排斥是食管癌中异常 SOX2 过表达的潜在机制。我们的研究还表明 HSP90 抑制剂可作为 SOX2 阳性癌症的潜在治疗药物。我们进一步证明 CHIP 主要在核区室中催化 SOX2 泛素化和降解。综上所述，我们的研究已确定 CHIP 是 SOX2 蛋白稳定性和致瘤活性的关键抑制因子，并揭示 CHIP 核排斥是食管癌中异常 SOX2 过表达的潜在机制。我们的研究还表明 HSP90 抑制剂可作为 SOX2 阳性癌症的潜在治疗药物。