Oncotarget

Research Papers:

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

Fuyumi Kato, Francesco Paolo Fiorentino, Andreu Alibés, Manuel Perucho, Montse Sánchez-Céspedes, Takashi Kohno and Jun Yokota _

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Oncotarget. 2016; 7:77378-77388. https://doi.org/10.18632/oncotarget.12671

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Abstract

Fuyumi Kato1, Francesco Paolo Fiorentino1, Andreu Alibés1, Manuel Perucho1, Montse Sánchez-Céspedes2, Takashi Kohno3, Jun Yokota1,3

1Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain

2Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain

3Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

Correspondence to:

Jun Yokota, email: [email protected]

Keywords: small cell lung cancer, MYCL, JQ1, CDK6, cell cycle arrest

Received: July 26, 2016    Accepted: September 29, 2016    Published: October 14, 2016

ABSTRACT

We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values ≤1.23 μM, with six of them showing GI50 values <0.1 μM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells.


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