Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers.
Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers.
复制标题
Junctophilin 3 (JPH3) 作为一种新型肿瘤抑制剂，在消化道癌症中经常被启动子 CpG 甲基化失活。
作者：
Hu X;Kuang Y;Li L;Tang H;Shi Q;Shu X;Zhang Y;Chan FK;Tao Q;He C
嗜连接蛋白（JPH）蛋白稳定质膜和内质网之间的连接膜复合物，也涉及一些人类疾病。JPH 3突变与亨廷顿病样2综合征有关通过对结肠癌细胞系对（HCT 116和DKO）的表观基因组学研究，我们鉴定了JPH 3作为16q24处的甲基化的新肿瘤抑制基因（TSG）候选基因。我们进一步研究了其表观遗传学改变及其在消化道肿瘤发生中的作用。在结直肠癌和胃癌中，由于其启动子CpG甲基化，发现RNA水平的JPH3表达经常沉默或减少，这与消化道癌患者的肿瘤进展和生存率低有关。JPH 3的异位表达在体外和体内抑制肿瘤细胞的生长。JPH 3表达上调胞浆Ca 2+水平，并在内质网应激后未折叠蛋白反应基因表达。JPH 3还诱导钙蛋白酶激活和随后的线粒体膜去极化和细胞凋亡。因此，JPH 3被鉴定为在结肠直肠和胃肿瘤中甲基化的新型TSG，其促进直肠介导的细胞凋亡，也作为消化道癌症的潜在转移和存活生物标志物。
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.