Ligand-independent EphA2 contributes to chemoresistance in small-cell lung cancer by enhancing PRMT1-mediated SOX2 methylation.

Chemoresistance is the crux of clinical treatment failure of small-cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin-producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand-independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand-independent manner rather than a ligand-dependent manner. Ligand-independent EphA2 enhanced the expression of stemness-associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial-mesenchymal transition (EMT) and reinforced self-renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co-immunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti-tumor effect with chemotherapy in preclinical models, including patient-derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment.

LiBis: an ultrasensitive alignment augmentation for low-input bisulfite sequencing.

The cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.

Genomic and immunological profiles of small-cell lung cancer between East Asians and Caucasian.

The characterization of immunological and genomic differences in small-cell lung cancer (SCLC) between East Asian (EA) and Caucasian patients can reveal important clinical therapies for EA patients with SCLC. By sequencing and analyzing a molecular and immunological dataset of 98-SCLC patients of EA ancestry, immunogenicity, including DNA damage repair alterations and tumor mutation burden (TMB), was found to be significantly higher in the EA cohort than in the Caucasian cohort. The epithelial-mesenchymal transition (EMT) was the signaling signature with the predominant frequency of mutations across all patients in the EA cohort. Analysis of tumor-infiltrated immune cells revealed that resting lymphocytes were significantly enriched in the EA cohort. Compound-targeting analysis showed that topoisomerase inhibitors might be capable of targeting TP53 and RB1 comutations in EA SCLC patients. EA SCLC patients who harbored COL6A6 mutations had poor survival, while Caucasian SCLC patients with OTOF, ANKRD30B, and TECPR2 mutations were identified to have a shorter survival.

Relationship between ATOH1 and tumor microenvironment in colon adenocarcinoma patients with different microsatellite instability status.

BACKGROUND: Colon adenocarcinoma (COAD) is one of the major varieties of malignant tumors threatening human health today. Immune checkpoint inhibitors (ICIs) have recently begun to emerge as an effective option for the treatment of COAD patients, but not all patients can benefit from ICI treatment. Previous studies have suggested that ICIs boast significant clinical effects on patients with microsatellite instability-high (MSI-H), while conversely patients with microsatellite-stable/microsatellite instability-low (MSS/MSI-L) have shown limited response. METHODS: We used ATAC-seq, RNA-seq, and mutation data from The Cancer Genome Atlas Colon adenocarcinoma (TCGA-COAD) cohort to perform multi-omics differential analysis on COAD samples with different MSI statuses, then further screened genes by additionally combining these results with survival analysis. We analyzed the effects of the screened genes on the tumor microenvironment and immunogenicity of COAD patients, and subsequently determined their influence on the efficacy of ICIs in COAD patients using a series of predictive indexes. RESULTS: Twelve genes were screened in the TCGA-COAD cohort, and after the combined survival analysis, we identified ATOH1 as having significant effects. ATOH1 is characterized by high chromatin accessibility, high expression, and high mutation in COAD patients in the MSI-H group. COAD patients with high ATOH1 expression are associated with a better prognosis, unique immune microenvironment, and higher efficacy in ICI treatment. Enrichment analysis showed that COAD patients with high ATOH1 expression displayed significant upregulation in their humoral immunity and other related pathways. CONCLUSIONS: We speculate that ATOH1 may influence the efficacy of ICIs therapy in patients with COAD by affecting the immune microenvironment and immunogenicity of the tumor.

Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4-6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients.

WITHDRAWN: lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance in SCLC: Potential molecular panel for targeted therapy.

This article has been withdrawn at the request of the editor-in-chief. Following publication of this article, the editor-in-chief discovered evidence of image duplication in Figures 1I, 1J, 3F, S5B, and S6B. Given the duplication of several western blots representing several gene products, the editor-in-chief has lost faith in the findings presented in this article. The authors maintain that these image duplications were the result of errors in file management and do not affect the conclusions of the study. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

A nomogram prognostic index for risk-stratification in diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation. RESULTS: Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone. CONCLUSIONS: We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients.

ZFHX3 mutation as a protective biomarker for immune checkpoint blockade in non-small cell lung cancer.

To date, immunotherapy has opened a new chapter in the treatment of lung cancer. Precise biomarkers can help to screen subpopulations of lung cancer to provide the best treatment. Multiple studies suggest that specific gene mutations may be predictive markers in guiding non-small cell lung cancer (NSCLC) immune checkpoint inhibitor (ICI) treatment. A published immunotherapy cohort with mutational and survival data for 350 NSCLC patients was used. First, the mutational data of the immunotherapy cohort were used to identify gene mutations related to the prognosis of ICI therapy. The immunotherapy cohort and TCGA-NSCLC cohort were further studied to elucidate the relationships between specific gene mutations and tumor immunogenicity, antitumor immune response capabilities, and immune cell and mutation counts in the DNA damage response (DDR) pathway. In the immunotherapy cohort (N = 350), ZFHX3 mutations were an independent predictive biomarker for NSCLC patients receiving ICI treatment. Significant differences were observed between ZFHX3-mutant (ZFHX3-MT) and ZFHX3-wild type (ZFHX3-WT) patients regarding the overall survival (OS) time (P < 0.001, HR = 0.26, 95% Cl 0.17-0.41). ZFHX3-MT is significantly associated with higher tumor mutation burden (TMB) and neoantigen load (NAL), and ZFHX3-MT positively correlates with known immunotherapy response biomarkers, including T-cell infiltration, immune-related gene expression, and mutation counts in the DDR pathway in NSCLC. ZFHX3-MT is closely related to longer OS in NSCLC patients treated with ICIs, suggesting that ZFHX3 mutations be used as a novel predictive marker in guiding NSCLC ICI treatment.

FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.

Fibroblast growth factor receptor-like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small-cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up-regulated in multidrug-resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental cells (H69 and H446). In addition, clinical samples showed that FGFRL1 was overexpressed in SCLC tissues, and high FGFRL1 expression was associated with the clinical stage, chemotherapy response and survival time of SCLC patients. Knockdown of FGFRL1 in chemoresistant SCLC cells increased chemosensitivity by increasing cell apoptosis and cell cycle arrest, whereas overexpression of FGFRL1 in chemosensitive SCLC cells produced the opposite results. Mechanistic investigations showed that FGFRL1 interacts with ENO1, and FGFRL1 was found to regulate the expression of ENO1 and its downstream signalling pathway (the PI3K/Akt pathway) in SCLC cells. In brief, our study demonstrated that FGFRL1 modulates chemoresistance of SCLC by regulating the ENO1-PI3K/Akt pathway. FGFRL1 may be a predictor and a potential therapeutic target for chemoresistance in SCLC.

Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas.

OBJECTIVE: Approximately 15-25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status. METHODS: The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined. RESULTS: BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xenografts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCA1-deficient tumors compared to BRCA1-proficient tumors. CONCLUSIONS: These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCA1-deficiencies.

Inhibition of N-acetylglucosaminyltransferase V enhances the cetuximab-induced radiosensitivity of nasopharyngeal carcinoma cells likely through EGFR N-glycan alterations.

N-acetylglucosaminyltransferase V (GnT-V), an enzyme that catalyzes the formation of the N-linked ß-1-6 branching of oligosaccharides, is related to the radiosensitivity of nasopharyngeal carcinoma (NPC). Cetuximab (C225) is an epidermal growth factor receptor (EGFR) inhibitor used as a radiosensitizer in the treatment of NPC. In this study, we used GnT-V as a molecular target to further sensitize cetuximab-treated NPC cells to radiation. The results from two NPC cell lines (CNE1 and CNE2) revealed that the silencing of GnT-V enhanced cetuximab-induced radiosensitivity by decreasing the ß-1-6 branching of oligosaccharides on the EGFR. GnT-V down-regulation combined with cetuximab decreased the survival fraction, healing rate and cell viability and increased the apoptosis rate. Concomitantly, the combination of cetuximab and irradiation did not change the EGFR mRNA and protein levels and decreased the ß-1-6 branching on the EGFR. Subsequently, we further explored the signaling downstream of EGF, particularly the PI3K/Akt signaling pathway, and discovered that treatment consisting of GnT-V down-regulation, irradiation and cetuximab was negatively correlated with phospho-Akt and phspho-PI3K. Finally, an in vivo experiment with radiotherapy revealed that the combination of GnT-V down-regulation and cetuximab decelerated tumor growth. In summary, our study demonstrated that the combination of decreased GnT-V activity and cetuximab enhanced NPC radiosensitivity, and the possible mechanism underlying this effect might involve the N-linked ß1-6 branching of the EGFR.

Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2.

BACKGROUND: Taurine upregulated gene1 (TUG1) as a 7.1-kb lncRNA, has been shown to play an oncogenic role in various cancers. However, the biological functions of lncRNA TUG1 in small cell lung cancer (SCLC) remain unknown. The aim of this study is to explore the roles of TUG1 in cell growth and chemoresistance of SCLC and its possible molecular mechanism. METHODS: The expression of TUG1 in thirty-three cases of SCLC tissues and SCLC cell line were examined by quantitative RT-PCR (qRT-PCR). The functional roles of TUG1 in SCLC were demonstrated by CCK8 assay, colony formation assay, wound healing assay and transwell assay, flow cytometry analysis and in vivo study through siRNA or shRNA mediated knockdown. Western blot assays were used to evaluate gene and protein expression in cell lines. Chromatin immunoprecipitation (ChIP) and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of TUG1 involved in cell growth and chemoresistance of small cell lung cancer. RESULTS: We found that TUG1 was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, downregulation of TUG1 expression could impair cell proliferation and increased cell sensitivity to anticancer drugs both in vitro and in vivo. We also discovered that TUG1 knockdown significantly promoted cell apoptosis and cell cycle arrest, and inhibited cell migration and invasion in vitro . We further demonstrated that TUG1 can regulate the expression of LIMK2b (a splice variant of LIM-kinase 2) via binding with enhancer of zeste homolog 2 (EZH2), and then promoted cell growth and chemoresistance of SCLC. CONCLUSIONS: Together, these results suggested that TUG1 mediates cell growth and chemoresistance of SCLC by regulating LIMK2b via EZH2.

A long non-coding RNA HOTTIP expression is associated with disease progression and predicts outcome in small cell lung cancer patients.

BACKGROUND: Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients. METHODS: RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo SCLC xenograft model in nude mice through HOTTIP loss- and gain-of-function effects. Western blot assay was used to evaluate gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression. RESULTS: We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of polycomb group protein EZH1. CONCLUSIONS: Overall, we identified that HOTTIP was involved in SCLC tumorigenesis through the ceRNA network "HOTTIP/miR-574-5p/EZH1". Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495.

Studies have shown that TSPAN12 serves as an oncogenic gene or tumor suppressor depending on the types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) is still unknown. In this study, we investigated whether TSPAN12 regulates chemoresistance, proliferation and tumor growth of SCLC under the regulation of miR-495 using two drug resistant cell lines. The results showed that down-regulation of TSPAN12 inhibited cells chemoresistance, proliferation and tumor growth. Besides, TSPAN12 elevation in SCLC specimens correlated with poor pathologic stage and shorter survival time. In addition, the dual luciferase assay indicated that TSPAN12 was one of the directly targeted genes of miR-495. Our study revealed that TSPAN12 promoted chemoresistance of SCLC under the regulation of miR-495. TSPAN12 depletion is a promising strategy for inhibiting the chemoresistance in SCLC.

Identification of DJ-1 as a contributor to multidrug resistance in human small-cell lung cancer using proteomic analysis.

Proteomic approaches have been proven to provide an important tool in identifying drug resistance-associated proteins. The aim of this study was to investigate the protein profiling of drug resistance-related proteins in small-cell lung cancer (SCLC) by proteomic analysis. The proteomic profiling was performed by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-TOF of SCLC in the multidrug-resistant cell line H69AR and its parental cell line H69. A total of 11 proteins were identified to be >2-fold up-or downregulated between the two cell lines. DJ-1, one of the differently expressed proteins identified by proteomics, was further examined by immunohistochemistry staining in 116 cases of SCLC tissues. Immunohistochemical results demonstrated that DJ-1 was expressed in 51.7% (60/116) of SCLC. DJ-1 expression was correlated significantly with survival time of SCLC patients (P < 0.05), but not with other clinical parameters such as gender, age and clinical stage (P > 0.05). Downregulation of DJ-1 using DJ-1-siRNA in H69AR cells sensitized cancer cells to chemotherapeutic drugs through increasing drug-induced cell apoptosis accompanied with G0-G1 phase arrest. These findings suggest DJ-1 may serve as a potential biomarker for chemoresistance and prognostic factor for patients with SCLC.

Targeted radionuclide therapy for lung cancer with iodine-131-labeled peptide in a nude-mouse model.

Integrin α3ß1 has been shown to be a novel candidate target for the imaging and specific therapy of non-small-cell lung cancer. We have previously reported on a peptide containing a novel motif of NGXG that specifically binds to the integrin α3 receptor on lung cancer cells using a one-bead one-peptide combinatorial library. In this study, we developed the peptide cNGEGQQc-based therapeutic agent labeling with radionuclide iodine-131 (I) and evaluated its characteristics including stability, biodistribution, antitumor activity, and safety. The results showed that I-cNGEGQQc was stable in serum. Furthermore, the biodistribution of I-cNGEGQQc was determined in normal mice and rabbits. In-vivo biodistribution studies showed that radiolabeled peptide in the kidney was significantly higher than that in other organs. Nude mice bearing lung cancer cell xenografts (H1975 and L78) were used as an in-vivo model for tumor-inhibition efficacy studies with I-cNGEGQQc. The tumor growth decreased significantly in mice receiving I-labeled peptide compared with the controls and the effect of I-labeled peptide can be blocked by unlabeled cNGEGQQc. Safety studies showed that I-cNGEGQQc was relatively safe for animals without significant toxicity. Our data suggest that I-cNGEGQQc has potential as a targeted radiotherapeutic agent for non-small-cell lung cancer.

[Role of TGF-ß1 in multi-drug resistance in small cell lung cancer and its clinical significance].

OBJECTIVE: To investigate the role of transforming growth factor ß1 (TGF-ß1) in multi-drug resistance in small cell lung cancer and its clinical significance.
 Methods: The mRNA and protein expressions of TGF-ß1 in H69 and H69AR cells were detected by real-time PCR and Western blot, respectively. After silence of TGF-ß1, the sensitivity of H69AR to drugs was detected by CCK8 assay. The expressions of TGF-ß1 in lung cancer and paracarcinoma tissues were examined by QRT-PCR and immunohistochemistry. The relationship of TGF-ß1 expression with clinical pathological features and prognosis of patients was studied.
 Results: Compared to H69, the mRNA and protein expressions of TGF-ß1 in H69AR cells were significantly increased by (5.93±0.47) and (8.49±1.92) folds, respectively (P<0.01). Transfection of TGF-ß1 siRNA resulted in a decrease of TGF-ß1 expression by 70.432% in H69AR cells (F=21.20, P<0.01) and an increase insensitivity to chemotherapeutic agents of H69AR cells (t=4.576, P<0.05). Compare with the paracarcinoma tissues, the expression of TGF-ß1 was significantly increased in small cell lung cancer tissues (t=13.925, P<0.01), which was closely related with clinical stage, chemosensitivity and overall survival (all P<0.05), but not related with gender, age (both P>0.05).
 Conclusion: TGF-ß1 is involved in the regulation of small cell lung cancer multidrug resistance, which may be a potential marker to evaluate the chemosensitivity and clinical prognostic for small cell lung cancer.

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells.

Homeobox (HOX) transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), has been reported to play an oncogenic role in various cancers including small cell lung cancer (SCLC). However, it is not known whether HOTAIR can modulate chemoresistance in SCLC. The aim of this study is to investigate the roles of HOTAIR in chemoresistance of SCLC and its possible molecular mechanism. Knockdown of HOTAIR was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on chemoresistance. The results showed that downregulation of HOTAIR increased cell sensitivity to anticancer drugs through increasing cell apoptosis and cell cycle arrest, and suppressed tumor growth in vivo. Moreover, HOXA1 methylation increased in the resistant cells using bisulfite sequencing PCR. Depletion of HOTAIR reduced HOXA1 methylation by decreasing DNMT1 and DNMT3b expression. The interaction between HOTAIR and HOXA1 was validated by RNA immunoprecipitation. Taken together, our study suggested that HOTAIR mediates chemoresistance of SCLC by regulating HOXA1 methylation and could be utilized as a potential target for new adjuvant therapies against chemoresistance.