Histone methyltransferase SETD1A participates in lung cancer progression

Abstract

Lung cancer is the leading cause of cancer‐related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5‐year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome‐related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial‐mesenchymal transition (EMT), as evidenced by inhibited WNT and transforming growth factor β (TGFβ) pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis

“…Recruitment of RbBP5 and formation of H3K4me3 at Snail TSS during EMT depend on the binding of SMAD2/3 and CBP at Snail TSS 59 . More recently, SETD1A was shown to promote lung cancer progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites 60 . Our current study provided mechanistic evidence of the involvement of H3K4me3 in EMT promotion through a direct physical interaction of an EMT-driving gene FOXQ1 and an MLL core complex subunit RbBP5 in both normal epithelial cells and TNBC cancers, suggesting the epigenetic machinery could be commonly implicated in tumor progression.…”

SETD1A‐mediated H3K4me3 methylation upregulates lncRNA HOXC‐AS3 and the binding of HOXC‐AS3 to EP300 and increases EP300 stability to suppress the ferroptosis of NSCLC cells

“…Targeting ferroptosis represents a new antitumor therapy and ferroptosis‐associated genes allow for effective NSCLC treatment 25 . Reportedly, SETD1A has the potential to be a drug target for lung cancer 9 . The current study underscored that SETD1‐mediated H3K4me3 modification upregulates lncRNA HOXC‐AS3 and thereafter enhances the binding of HOXC‐AS3 to EP300 and increasing EP300 stability, thus suppressing the ferroptosis of NSCLC cells (Figure 7).…”

“…SETD1A expression is upregulated in lung cancer, [9][10][11] but its effect on ferroptosis is unclear. To this end, we first examined SETD1A expression in cells and unveiled significantly increased SETD1A in NSCLC cells ( p < 0.05, Figure 1a,b).…”

“…SET domain containing 1A (SETD1A) is a histone methyltransferase that manipulates the subcellular localization of proteins related to the proliferation of many cancer cell types and thus oncogenesis 8 . In A549 and H1299 cells, SETD1A shows an increased expression trend 9 . In addition, SETD1A is essential for the proliferation of NSCLC cells during the progression to the S phase, thus contributing to NSCLC development 10,11 .…”

“…8 In A549 and H1299 cells, SETD1A shows an increased expression trend. 9 In addition, SETD1A is essential for the proliferation of NSCLC cells during the progression to the S phase, thus contributing to NSCLC development. 10,11 Nevertheless, its engagement in NSCLC cell ferroptosis is largely unknown.…”