An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer

Abstract

Background Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. Methods We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. Results Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. Conclusion Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.

Telomere maintenance genes-derived prognosis signature characterizes immune landscape and predicts prognosis of head and neck squamous cell carcinoma

“…[22] Additionally, evidence shows that genes such as paired box 5, aldehyde dehydrogenase 2 family member, and brain abundant membrane attached signal protein 1 are involved in cancer chemotherapy drug resistance. [23][24][25] Although immunotherapy has brought many benefits to patients with different types of cancer, developing a reliable method to identify immune therapy response is of significant clinical importance. [26,27] This study confirms the potential of a TMG-derived HNSCC subtype as an approach for identifying immune therapy response.…”

Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets

“…186 Wang et al found that the expression of ALDH2 is also upregulated in NSCLC cells, which is associated with cancer cell stemness property and paclitaxel resistance. 187 More implementation is needed to outline a possible role for ALDH2 in cancer.…”

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

“…Most of these proteins are ATP-driven multidrug efflux pumps such as MDR protein and P-glycoprotein (P-gp). After the intracellular drug binds to the transporter on the cell membrane, ATP hydrolysis drives a conformational change and pushes the drug out of the cell, resulting in the inability of the intracellular drug to accumulate in sufficient quantities to kill the cells [73] . Ruan et al used nanocarriers to reverse drug resistance induced by overexpression of the drug efflux pumps by inhibiting mitochondrial ATP synthesis [52] .…”

“…Ruan et al used nanocarriers to reverse drug resistance induced by overexpression of the drug efflux pumps by inhibiting mitochondrial ATP synthesis [ 52 ] . The cyclin-dependent kinase 6-phosphoinositide 3-kinase (CDK6-PI3K) signaling axis is an effective target for attenuating ATP binding cassette subfamily B member 1/P-gp-mediated MDR in cancer cells [ 11 , 74 , 75 ] .…”

“…Chen et al used synthetic NPs to destabilize microtubules and prevent the formation of spindles in normal mitosis, leading to abnormal cell division and eventually apoptosis [ 62 ] . Wang et al found that acetaldehyde dehydrogenase (ALDH2) gene was involved in mediating the RAF/MAPK signaling pathway, which is engaged in the regulation of apoptosis and drug sensitivity [ 74 ] .…”