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Theranostics 2017; 7(7):2150-2163. doi:10.7150/thno.18185 This issue Cite

Research Paper

Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers

Xiaotong Hu^1✉, Yeye Kuang¹, Lili Li², Haimei Tang¹, Qinglan Shi¹, Xingsheng Shu², Yanjiao Zhang², Francis KL Chan³, Qian Tao^2✉, Chao He¹

1. Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China;
2. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong;
3. Institute of Digestive Disease and State Key Laboratory of Digestive Diseases, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.

✉ Corresponding authors: X Hu, Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: (86) 571-86006363; Fax: (86) 571-86006363; E-mail: huxtcom; or Q Tao, Rm 315, Cancer Center, PWH, The Chinese University of Hong Kong, Shatin, Hong Kong. Tel: (852) 2632-1340; Fax: (852) 2648-8842; E-mail: qtaoedu.hk More

Abstract

Junctophilin (JPH) proteins stabilize junctional membrane complexes between plasma membrane and endoplasmic reticulum, also implicated in some human diseases. JPH3 mutations are linked to Huntington's disease-like 2 syndrome. Through epigenomic study of a colon cancer cell line pair (HCT116 and DKO), we identified JPH3 as a methylated novel tumor suppressor gene (TSG) candidate at 16q24. We further studied its epigenetic alterations and functions in digestive tumorigenesis. JPH3 expression at the RNA level was found to be frequently silenced or reduced in colorectal and gastric cancers due to its promoter CpG methylation, which is associated with tumor progression and poor survival of digestive cancer patients. Ectopic expression of JPH3 inhibited tumor cell growth in vitro and in vivo. JPH3 expression upregulated the cytosolic Ca²⁺ levels, and unfolded protein response gene expression upon endoplasmic reticulum stress. JPH3 also induced calpain activation and subsequent mitochondrial membrane depolarization and cell apoptosis. Thus, JPH3 was identified as a novel TSG methylated in colorectal and gastric tumors which promotes mitochondrial-mediated apoptosis, also as a potential metastasis and survival biomarker for digestive cancers.

Keywords: junctophilin, tumor suppressor gene, methylation, metastasis, 16q24.

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