Dataset Information

Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

ABSTRACT: Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.

SUBMITTER: Gardner EE

PROVIDER: S-EPMC5313262 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

Gardner Eric E EE Lok Benjamin H BH Schneeberger Valentina E VE Desmeules Patrice P Miles Linde A LA Arnold Paige K PK Ni Andy A Khodos Inna I de Stanchina Elisa E Nguyen Thuyen T Sage Julien J Campbell John E JE Ribich Scott S Rekhtman Natasha N Dowlati Afshin A Massion Pierre P PP Rudin Charles M CM Poirier John T JT

Cancer cell 20170201 2

Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked depo ...[more]

PMID: 28196596

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Project description:Long non-coding RNAs (lncRNAs) serve important regulatory roles in human tumors. The aim of the present study was to examine the role of ribonuclease P RNA component H1 (RPPH1) in non-small cell lung cancer (NSCLC). RPPH1 expression was assessed in datasets from The Cancer Genome Atlas, as well as lung cancer cell lines and patients with NSCLC. RPPH1 was significantly upregulated in NSCLC cell lines, compared with a normal lung epithelial cell line. Moreover, high RPPH1 expression was associated with poor overall survival and disease progression. RPPH1 was knocked down in A549 and H1299 cells using short hairpin (sh) RNA constructs, and the expressions of target genes and proteins were determined by reverse transcription-quantitative PCR and western blotting. Cell invasion potential was also determined using Transwell Matrigel assays. Compared with the negative control, RPPH1 silencing significantly reduced the number of invading cells, increased E-cadherin expression and reduced vimentin protein expression. Cell resistance to cisplatin/cis-diamminedichloridoplatinum (CDDP) was also evaluated using Cell Counting Kit-8 and colony formation assays. RPPH1 overexpression increased the resistance of A549 and H1299 cells to CDDP. Moreover, the potential interactions between RPPH1, microRNA (miR)-326 and Wnt family member 2B (WNT2B) were investigated using luciferase reporter assays and co-transfection experiments. MiR-326 expression was directly inhibited by RPPH1. In A549 cells co-transfected with shRPPH1 and miR-326 inhibitor, the invading cell number significantly increased compared with cells transfected with shRPPH1 alone. In addition, E-cadherin expression levels were reduced, and vimentin was upregulated. MiR-326 overexpression partially reduced the resistance of A549 cells to CDDP induced by RPPH1 overexpression. WNT2B expression was directly suppressed using miR-326. A549 cells co-transfected with a miR-326 mimic and a WNT2B overexpression vector demonstrated increased invasion potential, reduced E-cadherin and increased vimentin protein expression levels, compared with cells transfected with the mimic alone. miR-326 overexpression reduced CDDP resistance in A549 cells. However, co-transfection with WNT2B partially enhanced CDDP resistance, compared with the mimic alone. In conclusion, RPPH1 promoted NSCLC progression and lung cancer cell resistance to CDDP through miR-326 and WNT2B.

Dataset Information

Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

Publications

Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

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