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ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

ABSTRACT: In order to investigate epigenetic mechanisms contributing to stemness/pluripotency in lung cancers and potentially identify novel therapeutic targets in these malignancies, induced pluripotent stem cells (iPSCs) were generated from normal human small airway epithelial cells (SAEC) by lentiviral transduction of Oct4, SOX2, KLF4, and MYC (Yamanaka factors). The lung iPSC (Lu-iPSC) exhibited hallmarks of pluripotency including morphology, surface antigen and stem cell gene expression, in-vitro proliferation, and teratoma formation. Additionally, Lu-iPSC exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, up-regulation of genes encoding components of polycomb repressive complex 2 (PRC2), hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental SAEC. Additional Sex Combs Like-3 (ASXL3), encoding a PRC2 associated protein not previously described in reprogrammed cells, was markedly up-regulated in Lu-iPSC as well as human small cell lung cancer (SCLC) lines and specimens. ASXL3 over-expression correlated with increased genomic copy number in SCLC lines. Knock-down of ASXL3 inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSC, and significantly diminished in-vitro clonogenicity and growth of SCLC cells in-vivo. Collectively, these studies highlight the potential utility of this Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and suggest that ASXL3 is a novel target for SCLC therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102726 | GEO | 2017/10/31

SECONDARY ACCESSION(S): PRJNA398508

REPOSITORIES: GEO

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Project description:Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis due to early dissemination and rapid growth. We here analyze gene expression profile of 23 clinical SCLC samples. EZH2 was found to be highly expressed in SCLC samples compared to 42 normal tissues including the normal lung, and other PRC2 members, SUZ12 and EED, were also highly expressed in SCLC. To obtain target genes of PRC2 in SCLC, H3K27me3 mark was mapped in three SCLC cell lines, Lu130, H209 and DMS53, and compared to normal small airway epithelial cells (SAEC). Whereas H3K27me3(+) genes in SAEC were significantly overlapped with PRC-target genes in ES cells (P=1.7x10-31), genes with H3K27me3 in SCLC cell lines but not in SAEC were not significantly overlapped with PRC-target genes in ES cells (P=0.64). These genes with H3K27me3 specifically in SCLC cell lines but not in SAEC showed decreased expression, not only in SCLC cell lines but also in clinical SCLCs, and showed enrichment of GO-terms such as plasma membrane (P=8.1x10-21) and cell adhesion (P=1.7x10-8). Introduction of JUB, a gene showing specific H3K27me3 modification and the strongest repression in the three SCLC cell lines, resulted in repression of cellular growth in DMS53. In clinical SCLC cases, lower JUB level correlated to shorter survival (P=0.002), or a set of PRC target genes (JUB, EPHB4) and marker genes of classic type SCLC (GRP, ASCL1) correlated to shorter survival (P=0.0001) and classified SCLC into two groups with distinct prognosis. Growth of SCLC cell lines was repressed when treated with 3-Deazaneplanocin A, an inhibitor against PRC2. It is suggested that high expression of PRC2 in SCLC contributed to repression of genes including non-PRC-target genes in ES cells, and that the gene repression may play a role in genesis of SCLC. Gene expression in 23 clinical SCLC samples, 42 normal tissue samples, 3 small cell lung cancer (SCLC) cell lines, and normal small airway epithelial cell (SAEC) was analyzed by Affymetrix arrays. This dataset is part of the TransQST collection.

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ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

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