FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1.

Head and neck squamous cell carcinoma (HNSCC) still lacks effective targeted treatment. Therefore, exploring novel and robust molecular targets is critical for improving the clinical outcome of HNSCC. Here, we reported that the expression levels of family with sequence similarity 64, member A (FAM64A) were significantly higher in HNSCC tissues and cell lines. In addition, FAM64A overexpression was found to be strongly associated with an unfavorable prognosis of HNSCC. Both in vitro and in vivo evidence showed that FAM64A depletion suppressed the malignant activities of HNSCC cells, and vice versa. Moreover, we found that the FAM64A level was progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic 4-nitroquinoline-1-oxide mouse model. Mechanistically, a physical interaction was found between FAM64A and forkhead box protein M1 (FOXM1) in HNSCC cells. FAM64A promoted HNSCC tumorigenesis not only by enhancing the transcriptional activity of FOXM1, but also, more importantly, by modulating FOXM1 expression via the autoregulation loop. Furthermore, a positive correlation between FAM64A and FOXM1 was found in multiple independent cohorts. Taken together, our findings reveal a previously unknown mechanism behind the activation of FOXM1 in HNSCC, and FAM64A might be a promising molecular therapeutic target for treating HNSCC.

头颈部鳞状细胞癌（HNSCC）仍然缺乏有效的靶向治疗。因此，探索新的且可靠的分子靶点对于改善HNSCC的临床疗效至关重要。在此，我们报道序列相似性64家族成员A（FAM64A）在HNSCC组织和细胞系中的表达水平显著升高。此外，发现FAM64A过表达与HNSCC不良预后密切相关。体外和体内的证据均表明，FAM64A缺失抑制了HNSCC细胞的恶性活动，反之亦然。而且，我们发现在致癌的4 - 硝基喹啉 - 1 - 氧化物小鼠模型中，从正常组织到发育异常组织再到癌组织，FAM64A水平逐渐升高。从机制上讲，在HNSCC细胞中发现FAM64A与叉头框蛋白M1（FOXM1）之间存在物理相互作用。FAM64A不仅通过增强FOXM1的转录活性，而且更重要的是，通过自身调节回路调节FOXM1的表达来促进HNSCC的肿瘤发生。此外，在多个独立队列中发现FAM64A与FOXM1之间呈正相关。综上所述，我们的研究结果揭示了HNSCC中FOXM1激活背后此前未知的机制，并且FAM64A可能是治疗HNSCC的一个有前景的分子治疗靶点。