Coke Oven Emission Exposure Triggers Malignant Transformation of Lung Epithelial Cells by SFTA1P-Dependent Alteration of Acetyl-CoA Metabolism

Exposure
to coke oven emissions (COEs) is an important environmental
factor in lung cancer. A previous study revealed that 20 μg/mL
COE exposure for 120 days could induce malignant transformation of
lung epithelial cells. However, the underlying mechanism remains unclear.
The epigenetic regulation of long noncoding RNAs (lncRNAs) plays an
important role in carcinogenesis. Changes in lncRNA expression during
COE-induced malignant transformation were detected, highlighting the
importance of gene–environment interactions in cancer. Here,
we identified that SFTA1P was downregulated in COE-induced
malignant transformation of lung epithelial cells. Interestingly,
this reduction was found to have a gradient effect on different stages
of cells of COE exposure. Moreover, we found that downregulation of SFTA1P expression in lung cancer was related to patients’
poor prognosis. Phenotypic studies have demonstrated that SFTA1P suppressed lung cancer cell proliferation in vitro
and in vivo. Further mechanistic studies revealed that SFTA1P directly interacts with ACSS2, an important enzyme responsible for
synthesizing acetyl-CoA, leading to abnormal acetyl-CoA metabolism
and affecting COE-induced lung carcinogenesis. COE-induced malignant
transformed cells or cells with the knockdown of SFTA1P showed significantly increased fatty acid and cholesterol levels,
while normal lung epithelial cells or cells with overexpression of SFTA1P showed substantially decreased fatty acid and cholesterol
levels. Moreover, transfection of ACSS2 into cells with overexpressing SFTA1P could rescue the SFTA1P-induced
cell phenotype. Our findings link SFTA1P-regulated
acetyl-CoA metabolism with COE-induced malignant transformation and
imply that SFTA1P could be an important biomarker
for early intervention and diagnosis of lung cancer.