FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1

Abstract

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.

FAM64A aggravates proliferation, invasion, lipid droplet formation, and chemoresistance in gastric cancer: A biomarker for aggressiveness and a gene therapy target

“…FAM64A not only augmented the transcriptional activity of FOXM1 but also regulated FOXM1 expression through an autoregulatory loop, thereby promoting the tumorigenesis of HNSCC. Previously, FAM64A expression was found to upregulate in, osteosarcoma (Jiang, Zhou, et al, 2020), breast cancer (Yao et al, 2019), glioma (Wang et al, 2021), lung cancer (Jiang et al, 2021), cholangiocarcinoma (Jiang, Li, et al, 2020), and HNSCC (Zhao et al, 2022), in line with our data. FAM64A mRNA expression was found to negatively associate with the purity and loss infiltration of immune cells in GC and no immunopositivity of FAM64A was observed in the infiltrative immune cells, which accounted for the consistency between our morphological and molecular findings.…”

“…These effects were achieved by obstructing the negative feedback loop of NF‐κB/IκBα and facilitating the nuclear accumulation and transcriptional activity of NF‐κB. Zhao et al (2022) reported that FAM64A levels progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic mouse model induced by 4‐nitroquinoline‐1‐oxide. Physical interaction between FAM64A and FOXM1 (forkhead box protein M1) was uncovered in head and neck squamous cell carcinoma (HNSCC) cells as well.…”

“…Jiang et al (2021) discovered that the amount of FAM64A rose steadily from stage I to IV in lung adenocarcinoma. It has been suggested that FAM64A expression was significantly linked to a poorer prognosis in individuals suffering from neuroblastoma, osteosarcoma (Jiang, Zhou, et al, 2020), lung adenocarcinoma (Mizuno et al, 2020), cholangiocarcinoma (Jiang, Li, et al, 2020), and HNSCC (Zhao et al, 2022). Moreover, Jiao et al (2019) revealed that high FAM64A expression predicted shorter OS and recurrence‐free survival for pancreatic cancer patients, and was identified as an independent risk factor.…”

RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer

“…Because FOXM1 could be transcriptionally upregulated by itself ( 34 ), we further analyzed the correlation between RNF112 and FOXM1 in The Cancer Gene Atlas (TCGA) database. Notably, a marked inverse association between RNF112 and FOXM1 was noticed in gastric cancer compared with the other 32 tumor settings, indicating the RNF112/FOXM1 axis is relatively more important in gastric cancer ( Supplemental Figure 3A ).…”

Complex interaction and heterogeneity among cancer stem cells in head and neck squamous cell carcinoma revealed by single-cell sequencing

“…Squamous cell carcinoma of the head and neck (HNSCC) developed from the epithelium of the pharynx and oral mucosa is the sixth most common malignancy worldwide ( 1 ). The most closely associated causative factors for HNSCC include aging, exposure to environmental pollutants, family history, Epstein-Barr virus (EBV)/human papillomavirus (HPV) infection, and poor lifestyle habits, such as smoking and alcohol abuse ( 2 ). HPV (–) is the most common type of HNSCC and results in a worse prognostic outcome than (+) HNSCC ( 3 ).…”