ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Augustyn, Alexander; Borromeo, Mark D.; Wang, Tao; Fujimoto, Junya; Shao, Chunli; Dospoy, Patrick; Lee, Victoria; Tan, Christopher; Sullivan, James P.; Larsen, Jill E.; Girard, Luc; Behrens, Carmen; Wistuba, Ignacio I.; Xie, Yang; Cobb, Melanie H.; Gazdar, Adi F.; Johnson, Jane E.; Minna, John D.

doi:10.1073/pnas.1410419111

Cited by 219 publications

(267 citation statements)

References 37 publications

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“…Knockdown of ASCL1 in the SCLC cell line DMS53 resulted in inhibition of cell proliferation, providing additional support for a critical function of ASCL1 in SCLC. Our observation with DMS53 cells is consistent with previous reports that lung cancer cells with ASCL1 upregulation are sensitive to ASCL1 siRNA knockdown (18,32). Our results have, therefore, provided further validation of ASCL1 as a driver of proliferation in SCLC.…”

Section: Discussionsupporting

confidence: 92%

“…S8A). These two NSCLC cell lines are documented to be neuroendocrine in histology, and their ASCL1 mRNA abundance is consistent with the suggestion that ASCL1 is a lineage-specific marker for lung tumor cells with neuroendocrine features (18,29). Treatment of the neuroendocrine cell line UMC-11 with JQ1 also resulted in reduction of ASCL1 expression (Supplementary Fig.…”

Section: Brd4 Binds Directly To the Ascl1 Gene And Enhancersupporting

confidence: 84%

“…Overexpression of ASCL1 transcript was previously reported in SCLC and in lung tumors of neuroendocrine origin (17,18). We have shown that ASCL1 is highly expressed in SCLC cell lines that are sensitive to JQ1, and JQ1 treatment results in a rapid and reversible inhibition of ASCL1 gene expression.…”

Section: Discussionsupporting

confidence: 55%

“…Through gene-expression profiling analyses, we identified achaete-scute homolog-1 (ASCL1) to be a BET target gene specifically expressed in BET-sensitive SCLC. ASCL1 is a basic helix-loop-helix transcription factor important to early development of neuroendocrine progenitor cells and in cancer cells with neuroendocrine features (16)(17)(18). Here, we show that JQ1 inhibits the growth of SCLC cells by downregulating ASCL1 gene expression.…”

Section: Introductionmentioning

confidence: 71%

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Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Lenhart

Kirov

Desilva

et al. 2015

Molecular Cancer Therapeutics

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The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.

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Section: Discussionsupporting

confidence: 92%

Section: Brd4 Binds Directly To the Ascl1 Gene And Enhancersupporting

confidence: 84%

Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 71%

See 2 more Smart Citations

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Lenhart

Kirov

Desilva

et al. 2015

Molecular Cancer Therapeutics

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“…Bcl-2 acts as an anti-apoptotic factor but also contributes to the HIF-1a/Epo/EpoR/Bcl-2 system involved in angiogenesis [23]. hASH1 activates BCL-2 transcription, so Bcl-2 inhibitors are promising candidates for treatment of high-grade ONB; also blocking of hASH1 can potentially block Bcl-2 activity [24]. In one single study Bcl-2 expression in ONB tended to be related with better response to neoadjuvant chemotherapy, but also with poorer prognosis [25].…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

2016

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Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data.

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Comparative analysis of TTF‐1 binding DNA regions in small‐cell lung cancer and non‐small‐cell lung cancer

et al. 2019

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Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.

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ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Cited by 219 publications

References 37 publications

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Comparative analysis of TTF‐1 binding DNA regions in small‐cell lung cancer and non‐small‐cell lung cancer

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