HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer

Abstract

The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) plays a critical role in tumorigenesis as well as drug resistance in various cancers. However, the molecular mechanism by which HOTAIR induces gefitinib resistance in non-small cell lung cancer is to date unclear. In the present study, we revealed that HOTAIR is upregulated in gefitinib-resistant lung cancer cells and over-expression of HOTAIR enhances gefitinib resistance in lung cancer cells. In addition, the overexpression of HOTAIR promotes cell cycle progression through epigenetic regulation of EZH2/H3K27. Silencing of EZH2 by either siRNA or inhibitors sensitized the lung cancer cells to gefitinib. Inhibition of EZH2 induces expression of p16 and p21, whereas levels of CDK4, cyclinD1, E2F1, and LSD1 are significantly decreased in PC-9 cells overexpressing HOTAIR. ChIP-PCR experiments indicate that HOTAIR increases H3K27me3 recruitment to the promoter of p16 and p21 in PC-9 lung cancer cells overexpressing HOTAIR. In xenograft mouse models, overexpressing HOTAIR in lung cancer tissues decreased p16 and p21 proteins. Taken together, these data suggest that HOTAIR contributes to gefitinib resistance by regulating EZH2 and p16 and p21. Targeting HOTAIR may be a novel therapeutic strategy for treating gefitinib-resistance in non-small cell lung cancer.

PEG-4000 formed polymeric nanoparticles loaded with cetuximab downregulate p21 & stathmin-1 gene expression in cancer cell lines

“…p21 is a well-known WAF1/CIP1 (activating factor/cyclindependent kinase inhibitory protein-1) that was found to be vital for modulating cell cycle progression [17,18]. Early research on non-small cell lung cancer (NSCLC) revealed that in well-differentiated tumors, p21 is overexpressed [19] and stimulates tumor growth suppression via p53 activity, consistent with its cell cycle arrest activity [20]. Nevertheless, other studies have suggested that some pathways are not dependent on p53 and lead to p21 induction [20].…”

Histone H3 lysine-trimethylation markers are decreased by recombinant methioninase and increased by methotrexate at concentrations which inhibit methionine-addicted osteosarcoma cell proliferation

“…There are reported effects of drugs on histone H3 lysine-methylation, including H3K9me3 and H3K27me3 [ [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] ], which are inconsistent. There are no reports on the effect of MTX on histone-H3 lysine-methylation.…”

“…We previously reported that the levels of the histone H3K9me3 and H3K27me3 were decreased in methionine-addicted cancer cells when treated with rMETase [ 3 , 10 ]. There are previous reports on the relationship of drug resistance and the levels of H3K9me3 and H3K27me3, but they are not consistent [ [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] ]. There are no reports on the effect of MTX on histone H3 lysine-methylation.…”

Targeting epigenetic regulators to overcome drug resistance in cancers

“…8). [269][270][271][272] Zheng et al found that the poor prognosis in NSCLC patients was closely related to overexpression of LncRNA FTH1P3, which can inhibit TIMP3 protein by recruiting LSD1 and increased cell resistance to gefitinib. 269 Moreover, HAS2-AS1 also inhibited EphB3 by recruiting LSD1, promoting tumorigenesis and gefitinib-resistance in NSCLC.…”