Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer

Abstract

Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2 0 -deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

Dysfunction of phospholipase Cγ in immune disorders and cancer

“…The new findings support diverse, and sometime opposing roles of different PLC isoforms, in particular in cancer [20][21][22][32][33][34][35][36][37], and indicate that the generation of isozyme-specific inhibitors is highly desirable. Nevertheless, recent studies of the gain-of-function mutations that affect auto-inhibitory surfaces ( Figure 2) would imply that active site of these variants can be more exposed and accessible, suggests the possibility that more general PLC inhibitors could also be effective.…”

Epigenetic inactivation of PLCD1 in chronic myeloid leukemia

“…Multiple TSGs at 3p have been reported, such as BLU, DLEC1, PLCD1, FHIT, RASSFIA, CACNA2D2 (4)(5)(6)(13)(14)(15), and these TSGs are involved in the pathogenesis of various tumors such as gastrointestinal tract, lung, nasopharynx, esophagus, kidney, breast and cervix. Although these TSGs have been widely studied in many tumors, TSG PLCD1 with tumor-specific methylation has not been identified in CML.…”

“…Deletion of 3P is one of the most common genetic alterations in multiple cancers (2,3). It is believed that multiple TSGs are located in this important region, such as BLU, DLEC1 and PLCD1 (4)(5)(6).…”

“…The methylation of several TSGs, such as estrogen receptor (ER), death-associated protein kinase (DAPK1) and protein tyrosine phosphatase receptor typer (PTPRG), have been confirmed to be associated with the development and progression of chronic myeloid leukemia (CML) (10)(11)(12). Multiple TSGs at 3p have been reported, such as BLU, DLEC1, PLCD1, FHIT, RASSFIA, CACNA2D2 (4)(5)(6)(13)(14)(15) and these TSGs are involved in the pathogenesis of various tumors. Although these TSGs have been widely studied in many tumors, TSG PLCD1 with tumor-specific methylation has not been identified in CML, which would be worthy of further exploring to identify novel diagnostic biomarkers and therapeutic strategies for this tumor.…”

Curcumin-encapsulated polymeric nanoparticles for metastatic osteosarcoma cells treatment

“…Increased level of MMP7 was correlated with the presence of metastasis and poor patients' survival in colorectal, bladder and renal cell cancer [30]. This kind of matrix-degrading enzyme, MMP7, contributes to the invasion of many types of malignant cancer cells [31][32][33]. Down regulation of cMyc and MMP7 is thought to be an effective method to inhibit the proliferation and prevent the invasion of cancer cells [30,32,34].…”