Histone demethylase KDM5A enhances cell proliferation, induces EMT in lung adenocarcinoma cells, and have a strong causal association with paclitaxel resistance

Abstract

Recent reports suggest that histone demethylase KDM5A emerges as a new player in the development of drug resistance and thus increases the challenges of chemotherapy. Here, we explore the role of KDM5A in cell proliferation, epithelial-mesenchymal transition (EMT)and its causal association with paclitaxel resistance in lung adenocarcinoma. Paclitaxel-resistant lung adenocarcinoma PTX-Calu-3 cells showed significantly higher IC50 value (7±0.176 µM) upon paclitaxel treatment than lung adenocarcinoma SK-LI-1 (3.6±0.005 nM), Calu-3 (4.3±0.015 nM), and A549 (4.5±0.106 nM) cells. We found that expression of KDM5A and P-glycoprotein (P-gp), which plays a critical role in the development of paclitaxel resistance, were significantly higher in PTX-Calu-3 cells compared to SK-LI-1, Calu-3, and A549 cells.. We observed a significant increase in the expression of mesenchymal markers N-cadherin and vimentin, and a concomitant decrease in expression of E-cadherin and α-catenin in PTX-Calu-3 compared to SK-LI-1, Calu-3, and A549 lung cancer cell lines. Transwell Boyden chamber and wound healing assays further demonstrated that a significantly higher number of PTX-Calu-3 cells were invasive and motile compared to SK-LI-1, Calu-3, and A549 cells, thus supporting the role of KDM5A in metastasis-associated processes. Additionally, a significantly higher expression of KDM5A was observed in lung adenocarcinoma patients’ samples compared with adjacent normal tissues as well as in PTX-Calu-3 cells compared toSK-LI-1, Calu-3, and A549 cells, as shown both with histochemistry and real time-polymerase chain reaction (RT-PCR). In summary, these results suggest that KDM5A plays a key role in lung adenocarcinoma by promoting proliferation, EMT, and drug resistance to paclitaxel treatment.

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

“…[ 40,56 ] KDM5A is also known to regulate the transcription of many cancer associated genes but whether or not its DDR functions relate to those involving gene regulation is unclear (Figure 1B). [ 41,42 ]…”

“…[40,56] KDM5A is also known to regulate the transcription of many cancer associated genes but whether or not its DDR functions relate to those involving gene regulation is unclear (Figure 1B). [41,42] Considering the diverse roles of KDM5A in the DDR and in transcription, additional modes of regulation for KDM5A have been investigated. Recently, our work uncovered new regulatory elements controlling KDM5A functions in the DDR and damage-proximal transcriptional responses, which includes the involvement of PARP1 in promoting the recruitment of KDM5A to DSBs.…”

“…[119] Cancer and gene regula-tory functions of macroH2A have also been described to include DSB repair, [80] expression of EMT markers, [120] and chemoresistance [114] (Figure 4; reviewed in [114,121] ). Intriguingly, these functions are shared with KDM5A, including expression of cancer driving genes (including EMT markers), [41,42] proliferation and metastasis, [43] and chemoresistance (Figure 4). [46,47] Several scenarios exist which could explain the functional overlap between these factors.…”

“…[34,[38][39][40] KDM5A is also known to promote cancer through its ability to regulate gene expression. For example, KDM5A inhibits p53 expression, [41] regulates epithelial-to-mesenchymal transition (EMT) markers, [42] and impacts the expression of the cell cycle regulator p27. [43] Recently, KDM5A has gained attention for its role in promoting the progression of specific cancer types, including breast, [44] osteosarcoma, [43] and lung cancers, [42,45] all of which present with significantly elevated levels of KDM5A.…”

“…For example, KDM5A inhibits p53 expression, [41] regulates epithelial-to-mesenchymal transition (EMT) markers, [42] and impacts the expression of the cell cycle regulator p27. [43] Recently, KDM5A has gained attention for its role in promoting the progression of specific cancer types, including breast, [44] osteosarcoma, [43] and lung cancers, [42,45] all of which present with significantly elevated levels of KDM5A. [46][47][48] Additional cancers have been identified with KDM5A mutations and importantly, silencing of KDM5A expression can reduce tumor progression in some cancer-contexts (Figure 1B).…”