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

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.

The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42

“…Interestingly, a recent study reported that miR-370 also negatively modulated GINS4 expression 12. It would be meaningful to further investigate more regulators of GINS4 expression, including transcription factors, miRNAs, long non-coding RNAs, and circRNAs, and how these regulators interact with each other and contribute to gastric cancer growth and progression41, 42.…”

Evidence for calpains in cancer metastasis

“…Similarly, the integrin α2/FAK/ERK/μ-CAPN pathway is validated to be the mechanism in colon cancer motility (Sawhney et al, 2006). In addition to participate in cell senescence, Tiam 1 also affects AJ maintenance as (Hu et al, 2017). Reports have shown that several EMT markers are modulated after ER-stress-induced signaling pathways (Tanjore et al, 2015).…”

“…ER is universally recognized as an important cell factory inducing the proper folding of newly synthesized transmembrane proteins and the reservoir modulating of homeostasis. Given that tumor cells always reprogram their metabolism to sustain endless progression, the scarce energy or nutrients make tumor cells vulnerable to ER stress (Hu et al, ). Reports have shown that several EMT markers are modulated after ER‐stress‐induced signaling pathways (Tanjore et al, ).…”

“…modulating of homeostasis. Given that tumor cells always reprogram their metabolism to sustain endless progression, the scarce energy or nutrients make tumor cells vulnerable to ER stress (Hu et al, 2017). Reports have shown that several EMT markers are modulated after ER-stress-induced signaling pathways (Tanjore et al, 2015).…”

Junctophilins emerge as novel therapeutic targets

“…JP: junctophilin; mRNA: messenger RNA; SR: sarcoplasmic reticulum [Color figure can be viewed at wileyonlinelibrary.com] calcium homeostasis. In addition, JP3 suppresses Bcl2 and p-Akt(Hu et al, 2017).Takentogether, JP3 exhibits an inhibitory role in the growth and migration of gastrointestinal tumor cells. JP3 expression also has shown a strong correlation with disease development and low survival of patients with gastrointestinal cancer.…”