HOXD1 inhibits lung adenocarcinoma progression and is regulated by DNA methylation

The homeobox (HOX) gene family encodes a number of highly conserved transcription factors and serves a crucial role in embryonic development and tumorigenesis. Homeobox D1 (HOXD1) is a member of the HOX family, whose biological functions in lung cancer are currently unclear. The University of Alabama at Birmingham Cancer data analysis Portal of HOXD1 expression patterns demonstrated that HOXD1 was downregulated in lung adenocarcinoma (LUAD) patient samples compared with adjacent normal tissue. Western blotting analysis demonstrated low HOXD1 protein expression levels in lung LUAD cell lines. The Kaplan-Meier plotter database demonstrated that reduced HOXD1 expression levels in LUAD correlated with poorer overall survival. Meanwhile, an in vitro study showed that HOXD1 overexpression suppressed LUAD cell proliferation, migration and invasion. In a mouse tumor model, upregulated HOXD1 was demonstrated to inhibit tumor growth. In addition, targeted bisulfite sequencing and chromatin immunoprecipitation assays demonstrated that DNA hypermethylation occurred in the promoter region of the HOXD1 gene and was associated with the action of DNA methyltransferases. Moreover, upregulated HOXD1 served as a transcriptional factor and increased the transcriptional expression of bone morphogenic protein (BMP)2 and BMP6. Taken together, the dysregulation of HOXD1 mediated by DNA methylation inhibited the initiation and progression of LUAD by regulating the expression of BMP2/BMP6.