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.

中文翻译：

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junctophilin 3（JPH3）作为新型肿瘤抑制因子的表观基因组学和功能表征在消化道癌症中经常被启动子CpG甲基化失活。

junctophilin（JPH）蛋白可稳定质膜和内质网之间的连接膜复合物，这也与某些人类疾病有关。JPH3突变与亨廷顿氏病样2综合征相关。通过对结肠癌细胞系（HCT116和DKO）的表观基因组学研究，我们确定JPH3在16q24时是甲基化的新型抑癌基因（TSG）候选者。我们进一步研究了它的表观遗传学改变和在消化肿瘤发生中的功能。由于其启动子CpG甲基化，在结肠直肠癌和胃癌中发现JPH3在RNA水平的表达经常被沉默或降低，这与肿瘤的进展和消化道癌症患者的不良生存有关。JPH3的异位表达抑制肿瘤细胞的体外和体内生长。内质网应激后，JPH3表达上调了胞质Ca ^2+的水平，并展开了蛋白反应基因的表达。JPH3还诱导钙蛋白酶激活，随后线粒体膜去极化和细胞凋亡。因此，JPH3被鉴定为在结肠直肠和胃肿瘤中甲基化的新型TSG，可促进线粒体介导的细胞凋亡，也可作为消化道癌症的潜在转移和生存生物标志物。