Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition

Deshui Jia, Arnaud Augert, Dong Wook Kim, Emily Eastwood, Nan Wu, Ali H. Ibrahim, Kee Beom Kim, Colin T. Dunn, Smitha P.S. Pillai, Adi F Gazdar, Hamid Bolouri, Kwon Sik Park, David MacPherson

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy.Significance: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors. These data provide a rationale for selectively treating CREBBP-mutant SCLC with HDAC inhibitors. Cancer Discov; 8(11); 1422-37.

Original languageEnglish (US)
Pages (from-to)1422-1437
Number of pages16
JournalCancer Discovery
Volume8
Issue number11
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Oncology

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    Jia, D., Augert, A., Kim, D. W., Eastwood, E., Wu, N., Ibrahim, A. H., Kim, K. B., Dunn, C. T., Pillai, S. P. S., Gazdar, A. F., Bolouri, H., Park, K. S., & MacPherson, D. (2018). Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition. Cancer Discovery, 8(11), 1422-1437. https://doi.org/10.1158/2159-8290.CD-18-0385