Abstract
Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified gene associated with malignant tumor progression and patient chemotherapy resistance in human hepatocellular carcinoma (HCC). Previously, we found an association between CHD1L overexpression and poor patient survival in non-small-cell lung cancer (NSCLC). However, little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC. By employing immunohistochemistry, we analyzed the expression of CHD1L in NSCLC samples and elucidated the roles and mechanism of CHD1L in NSCLC chemoresistance. We found that the increased expression of CHD1L is positively correlated with a shorter survival time of patients who had received chemotherapy after surgery. We also found that the expression of CHD1L was increased after cisplatin treatment in A549 cells. Conversely, the depletion of CHD1L in cisplatin-resistance cells increased the cell sensitivity to cisplatin, indicating that CHD1L plays a critical role in cisplatin resistance of NSCLC cells. Importantly, we identified the ATP-Binding Cassette Sub-Family B Member (ABCB1) gene as a potential downstream target of CHD1L in NSCLC cells. Knocking down ABCB1 coupled with ectopic expression of CHD1L enhanced the effect of cisplatin on NSCLC cells apoptosis. In addition, overexpressed CHD1L increase the transcription of c-Jun which targeted directly to the promoter of ABCB1. Our data demonstrate that CHD1L could induce cisplatin resistance in NSCLC via c-Jun-ABCB1–NF-κB axis, and may serve as a novel predictive marker and the potential therapeutic target for cisplatin resistance in NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide[1]
We examined the expression of Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) using IHC in 233/248 (93.9%) of our Non-small-cell lung cancer (NSCLC) samples
In order to evaluate the association between CHD1L overexpression and the response to cisplatin-based chemotherapy in NSCLC patients, we further tested CHD1L expression by IHC in a restricted cohort of locally advanced NSCLC treated with cisplatinbased neoadjuvant chemotherapy (n = 30)
Summary
Non-small-cell lung cancer (NSCLC) consists of a largely heterogeneous group of following cisplatin treatment a high rate of relapse occurs despite so many efforts on overcoming drug resistance[5]. A better understanding of the molecular mechanisms underlying cisplatin resistance is crucial for optimizing the individual therapies and achieve better survival outcomes for NSCLC patients[6]. Official journal of the Cell Death Differentiation Association. We found that CHD1L expression is positively associated with tumor progression in HCC patients[8,9,10,11]. Our previous study showed that overexpression of CHD1L associated with the advanced diagnostic stage and poorer survival rate of NSCLC patients[17]. Little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC
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