RECQL4 regulates DNA damage response and redox homeostasis in esophageal cancer

Abstract

Objective: RECQL4 (a member of the RECQ helicase family) upregulation has been reported to be associated with tumor progressionin several malignancies. However, whether RECQL4 sustains esophageal squamous cell carcinoma (ESCC) has not been elucidated.In this study, we determined the functional role for RECQL4 in ESCC progression.

Methods: RECQL4 expression in clinical samples of ESCC was examined by immunohistochemistry. Cell proliferation, cellularsenescence, the epithelial-mesenchymal transition (EMT), DNA damage, and reactive oxygen species in ESCC cell lines withRECQL4 depletion or overexpression were analyzed. The levels of proteins involved in the DNA damage response (DDR), cell cycleprogression, survival, and the EMT were determined by Western blot analyses.

Results: RECQL4 was highly expressed in tumor tissues when compared to adjacent non-tumor tissues in ESCC (P < 0.001) andpositively correlated with poor differentiation (P = 0.011), enhanced invasion (P = 0.033), and metastasis (P = 0.048). RECQL4was positively associated with proliferation and migration in ESCC cells. Depletion of RECQL4 also inhibited growth of tumorxenografts in vivo. RECQL4 depletion induced G0/G1 phase arrest and cellular senescence. Importantly, the levels of DNA damageand reactive oxygen species were increased when RECQL4 was depleted. DDR, as measured by the activation of ATM, ATR, CHK1,and CHK2, was impaired. RECQL4 was also shown to promote the activation of AKT, ERK, and NF-kB in ESCC cells.

Conclusions: The results indicated that RECQL4 was highly expressed in ESCC and played critical roles in the regulation of DDR,redox homeostasis, and cell survival.