Wang Jingjing, Chen Yang, Sun Yunqing, Liu Hanzhe, Du Ruixue, Wang Xuewen, Shao Zhe, Liu Ke, Shang Zhengjun
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China.
Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Int J Biol Sci. 2025 Jan 1;21(2):671-684. doi: 10.7150/ijbs.95723. eCollection 2025.
FAT atypical cadherin 1 (), which encodes an atypical cadherin-coding protein, has a high mutation rate and is commonly regarded as a tumor suppressor gene in head and neck squamous cell carcinoma (HNSCC). Nonetheless, the potential regulatory mechanisms by which FAT1 influences the progression of HNSCC remain unresolved. In this context, we reported that FAT1 was downregulated in tumor tissues/cells compared with normal tissues/cells and that it was correlated with the clinicopathological features and prognosis of HNSCC. Knockdown of FAT1 enhanced cancer stem cell (CSC) properties and decreased the percentage of apoptotic tumor cells. Mechanistically, FAT1 knockdown increased the phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII), subsequently resulting in diminished interaction between phosphorylated STAT1 and interferon regulatory factor 9 (IRF9), which inactivated the interferon pathway and facilitated the adoption of the malignant phenotype of HNSCC cells. The overexpression of STAT1 and IRF9 alleviated the malignant behavior caused by FAT1 inhibition. In summary, our study reveals the role of FAT1 in suppressing the CSC properties of HNSCC via the CaMKII/STAT1/IRF9 pathway, and that targeting might be a promising treatment for HNSCC.
FAT非典型钙黏蛋白1（FAT1）编码一种非典型钙黏蛋白编码蛋白，其突变率高，在头颈部鳞状细胞癌（HNSCC）中通常被视为肿瘤抑制基因。然而，FAT1影响HNSCC进展的潜在调控机制仍未明确。在此背景下，我们报道与正常组织/细胞相比，FAT1在肿瘤组织/细胞中表达下调，且与HNSCC的临床病理特征及预后相关。敲低FAT1可增强癌症干细胞（CSC）特性并降低凋亡肿瘤细胞的比例。机制上，敲低FAT1会增加钙调蛋白依赖性蛋白激酶II（CaMKII）的磷酸化水平，随后导致磷酸化的信号转导和转录激活因子1（STAT1）与干扰素调节因子9（IRF9）之间的相互作用减弱，从而使干扰素途径失活并促进HNSCC细胞恶性表型的形成。STAT1和IRF9的过表达可减轻FAT1抑制引起的恶性行为。总之，我们的研究揭示了FAT1通过CaMKII/STAT1/IRF9途径在抑制HNSCC的CSC特性中的作用，并且靶向该途径可能是HNSCC的一种有前景的治疗方法。
