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Epigenetic Silencing of the Candidate Tumor Suppressor Gene Per1 in Non–Small Cell Lung Cancer

Authors' Affiliations: ¹ Division of Hematology/Oncology, Departments of ² Pathology and ³ Surgery, Cedars-Sinai Medical Center/University of California, Los Angeles School of Medicine, Los Angeles, California and ⁴ Department of Hematology/Respiratory, Kochi Medical School, Kochi, Japan

Requests for reprints: Sigal Gery, Cedars-Sinai Medical Center, Davis Building 5066, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-4609; Fax: 310-423-0225; E-mail: gerys{at}cshs.org.

Purpose: Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non–small cell lung cancer (NSCLC).

Experimental Design: We used microarray analysis to screen for tumor suppressor genes.

Results: We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC.

Conclusions: These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.

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