FANCD2 Confers a Malignant Phenotype in Esophageal Squamous Cell Carcinoma by Regulating Cell Cycle Progression

Simple Summary Fanconi anemia patients with germlineFANCD2defects are susceptible to cancers. In order to understandFANCD2function in esophageal cancers, we used cell line, animal model, and sequencing approaches. We knocked out theFANCD2gene and examined the functional impact of its loss on tumor growth and metastasis and performed assays for cell growth, cell cycle, and cellular localization.FANCD2promotes tumorigenesis in this cancer.FANCD2is significantly upregulated in tumors. Depletion of FANCD2 protein expression significantly suppresses the cancer cell proliferation and tumor colony formation and metastasis potential, as well as cell cycle progression, by involving specific cell signaling pathways. FANCD2 is moved out of the nucleus to the cytoplasm during cell cycle progression. We provide evidence of a novel role ofFANCD2in esophageal cancer progression and its potential value as a biomarker for disease management. Fanconi anemia patients with germline genetic defects inFANCD2are highly susceptible to cancers. Esophageal squamous cell carcinoma (ESCC) is a deadly cancer. Little is known about the function ofFANCD2in ESCC. For detailed molecular and mechanistic insights on the functional role ofFANCD2in ESCC, in vivo and in vitro assays and RNA sequencing approaches were used. Utilizing Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) technology,FANCD2knockout models were established to examine the functional impact in mouse models for tumor growth and metastasis and in vitro assays for cell growth, cell cycle, and cellular localization. Our RNA sequence analyses were integrated with public datasets.FANCD2confers a malignant phenotype in ESCC.FANCD2is significantly upregulated in ESCC tumors, as compared to normal counterparts. Depletion of FANCD2 protein expression significantly suppresses the cancer cell proliferation and tumor colony formation and metastasis potential, as well as cell cycle progression, by involving cyclin-CDK and ATR/ATM signaling. FANCD2 translocates from the nucleus to the cytoplasm during cell cycle progression. We provide evidence of a novel role ofFANCD2in ESCC tumor progression and its potential usefulness as a biomarker for ESCC disease management.