State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
Cancer Lett. 2024 Jul 10;594:216962. doi: 10.1016/j.canlet.2024.216962. Epub 2024 May 18.
PA28γ overexpression is aberrant and accompanied by poor patient prognosis in various cancers, the precise regulatory mechanism of this crucial gene in the tumor microenvironment remains incompletely understood. In this study, using oral squamous cell carcinoma as a model, we demonstrated that PA28γ exhibits high expression in cancer-associated fibroblasts (CAFs), and its expression significantly correlates with the severity of clinical indicators of malignancy. Remarkably, we found that elevated levels of secreted IGF2 from PA28γ CAFs can enhance stemness maintenance and promote tumor cell aggressiveness through the activation of the MAPK/AKT pathway in a paracrine manner. Mechanistically, PA28γ upregulates IGF2 expression by stabilizing the E2F3 protein, a transcription factor of IGF2. Further mechanistic insights reveal that HDAC1 predominantly mediates the deacetylation and subsequent ubiquitination and degradation of E2F3. Notably, PA28γ interacts with HDAC1 and accelerates its degradation via a 20S proteasome-dependent pathway. Additionally, PA28γ CAFs exert an impact on the tumor immune microenvironment by secreting IGF2. Excitingly, our study suggests that targeting PA28γ CAFs or secreted IGF2 could increase the efficacy of PD-L1 therapy. Thus, our findings reveal the pivotal role of PA28γ in cell interactions in the tumor microenvironment and propose novel strategies for augmenting the effectiveness of immune checkpoint blockade in oral squamous cell carcinoma.
PA28γ 的过表达在各种癌症中是异常的，并伴有患者预后不良，但其在肿瘤微环境中的关键基因的精确调控机制仍不完全清楚。在这项研究中，我们以口腔鳞状细胞癌为模型，证明了 PA28γ 在癌相关成纤维细胞（CAFs）中高表达，其表达与恶性临床指标的严重程度显著相关。值得注意的是，我们发现 PA28γ CAFs 分泌的 IGF2 水平升高，可以通过 MAPK/AKT 通路的旁分泌方式增强干性维持并促进肿瘤细胞侵袭性。在机制上，PA28γ 通过稳定 IGF2 的转录因子 E2F3 来上调 IGF2 的表达。进一步的机制研究表明，HDAC1 主要通过去乙酰化和随后的泛素化及降解 E2F3 来介导。值得注意的是，PA28γ 通过 20S 蛋白酶体依赖性途径与 HDAC1 相互作用并加速其降解。此外，PA28γ CAFs 通过分泌 IGF2 对肿瘤免疫微环境产生影响。令人兴奋的是，我们的研究表明，靶向 PA28γ CAFs 或分泌的 IGF2 可以提高 PD-L1 治疗的疗效。因此，我们的研究结果揭示了 PA28γ 在肿瘤微环境中细胞相互作用中的关键作用，并提出了增强免疫检查点阻断在口腔鳞状细胞癌中疗效的新策略。
