The pseudogene DUXAP10 contributes to gefitinib resistance in NSCLC by repressing OAS2 expression

Abstract

Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI),is the currently recommended first-line therapy for advanced EGFR-mutant lung cancer, and understanding the mechanism of resistance is the key to formulating therapeutic strategies for EGFR-TKIs. In this study, we evaluate the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance. We find that pseudogene DUXAP10 expression is significantly upregulated in NSCLC gefitinib-resistant cells and tissues. Gain and loss of function assays reveal that knockdown of DUXAP10 by siRNA reverses gefitinib resistance both in vitro and in vivo . Furthermore, DUXAP10 interacts with the histone methyltransferase enhancer of zeste homolog 2 (EZH2) to repress the expression of 2′,5′-oligoadenylate synthetase (OAS2). Overall, our study highlights the pivotal role of DUXAP10 in gefitinib resistance, and the DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC.

A Pan-Cancer Analysis Reveals OAS2 as a Biomarker for Cancer Prognosis and Immunotherapy

“…Further research in colorectal cancer has con rmed that OAS2 upregulates the expressions of E-cadherin, β-catenin, claudin-1 and snail, which induces autophagy and prolongs recurrence-free survival (RFS)(8). A recent study indicates that OAS2 plays a role in ge tinib resistance as a tumor suppressor (20). While in another study, downregulation of OAS2 promotes the sensitivity of acute myeloid leukemia cells to chemotherapy drugs (21).…”

circIARS: a potential plasma biomarker for diagnosing non-small cell lung cancer

“…In addition, although CT is noninvasive and highly sensitive, it is often accompanied by overdiagnosis [ 2 , 3 ]. Several studies have confirmed the effects of noncoding RNAs (ncRNAs) and mRNAs on the early screening and biological progression of NSCLC, such as the inhibition of growth, ING5 overexpression, miR-34c-5p/Snail1 inhibition of EMT and lung cancer cell invasion [4] , and on the pseudogene DUXAP10 which contributes to gefitinib resistance in NSCLC by inhibiting OAS2 expression [5] . Therefore, the screening of simple and efficient diagnostic markers and the development of minimally invasive techniques for the diagnosis of early-stage NSCLC are of great clinical importance.…”