American Association for Cancer Research
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Figures S1-S16 from Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition

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journal contribution
posted on 2023-04-03, 21:21 authored by 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

Supplementary Figures S1 to S16



American Cancer Society

David R. Jones Fund at University of Virginia



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. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333

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