FOXN3 is downregulated in osteosarcoma and transcriptionally regulates SIRT6, and suppresses migration and invasion in osteosarcoma

Abstract

Forkhead box N3 (FOXN3) has been reported to be downregulated in numerous cancers, including laryngeal, oral squamous cell and hepatocellular carcinomas, and diffuse large B-cell lymphoma. FOXN3 was proposed to serve as a tumor suppressor; however, the function of FOXN3 in osteosarcoma (OS) remains unknown. The present study suggested that FOXN3 was notably downregulated in OS tissues compared with in adjacent normal tissues, and the expression of FOXN3 was negatively correlated with tumor size, metastasis and tumor, node and metastasis stage. Additionally, low expression levels of FOXN3 predicted a poor prognosis of patients with OS. Additionally, the present study revealed that FOXN3 was also downregulated in OS cells. Numerous functional experiments, including colony formation, Cell Counting Kit-8, wound healing and Transwell invasion assays, were performed. The results of the present study revealed that FOXN3 suppressed the proliferation, migration and invasion of OS cells. SIRT6 has been reported to serve a key role in OS; chromatin-immunoprecipitation (ChIP) and quantitative ChIP, as well as a luciferase reporter assay, demonstrated that SIRT6 was transcriptionally regulated by FOXN3. Furthermore, FOXN3 also regulated matrix metalloproteinase-9 secretion via the regulation of SIRT6 expression. The findings of the present study indicated that FOXN3 serves as a tumor suppressor in OS and proposed FOXN3 as a prognostic predictor and a therapeutic target for patients with OS.

The clinical and prognostic significance of FOXN3 downregulation in acute myeloid leukaemia

“…28 In recent years, studies on FOXN3 have suggested that it may play dual roles in different tumours. Acting as a tumour suppressor gene, FOXN3 is reduced in several types of tumours, such as HCC, colon cancer and osteosarcoma, 9,10,19 but it is upregulated in ovarian cancer and breast cancer, where it acts as an oncogene. 11,29 One explanation for the diverse effects of FOXN3 may be due to the specific cellular and tissue environment.…”

“…The transcription factor forkhead box N3 (FOXN3), as a member of the forkhead box N superfamily, participates in several biological processes, including the cell cycle, cell differentiation, epithelial-mesenchymal transition, gene transcription and glucose metabolism. 9-13 Previous studies have shown that the downregulated expression of FOXN3 is observed in various malignancies, such as hepatocellular carcinoma (HCC), colon cancer, ERα-positive breast cancer, Hodgkin lymphoma, head and neck cancer, lung cancer, adult glioblastoma multiforme, T cell acute lymphoblastic leukaemia (ALL)and osteosarcoma, 9,10,12,[14][15][16][17][18][19] and the FOXN3 expression level is associated with the prognosis of some cancers. Abstract Introduction: The expression of forkhead box N3 (FOXN3), also known as checkpoint suppressor 1 (CHES1), is reduced in many types of tumours.…”

“…and osteosarcoma, 9,10,12,[14][15][16][17][18][19] and the FOXN3 expression level is associated with the prognosis of some cancers. Abstract Introduction: The expression of forkhead box N3 (FOXN3), also known as checkpoint suppressor 1 (CHES1), is reduced in many types of tumours.…”

Inhibition of SIRT6 Potentiates the Anti-Tumor Effect of Doxorubicin through Suppression of the DNA Damage Repair Pathway in Osteosarcoma

“…However, there have been limited studies on the roles of SIRT6 in osteosarcoma [32][33][34][35]. Furthermore, the role of SIRT6 in the progression of osteosarcoma has been reported controversially [32,33,35].…”

Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

“…In osteosarcoma cells, the PARP inhibitor, olaparib, potentiates the therapeutic e cacy of doxorubicin [31]. However, there have been limited studies on the roles of SIRT6 in osteosarcoma [32][33][34][35]. Furthermore, the role of SIRT6 in the progression of osteosarcoma has been reported controversially [32,33,35].…”