Gene Summary

Gene:PLCD1; phospholipase C delta 1
Aliases: NDNC3, PLC-III
Summary:This gene encodes a member of the phospholipase C family. Phospholipase C isozymes play critical roles in intracellular signal transduction by catalyzing the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). The encoded protein functions as a tumor suppressor in several types of cancer, and mutations in this gene are a cause of hereditary leukonychia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PLCD1 (cancer-related)

Li L, Xu J, Qiu G, et al.
Epigenomic characterization of a p53-regulated 3p22.2 tumor suppressor that inhibits STAT3 phosphorylation via protein docking and is frequently methylated in esophageal and other carcinomas.
Theranostics. 2018; 8(1):61-77 [PubMed] Free Access to Full Article Related Publications

You HL, Huang WT, Liu TT, et al.
Mutations of candidate tumor suppressor genes at chromosome 3p in intrahepatic cholangiocarcinoma.
Exp Mol Pathol. 2017; 103(3):249-254 [PubMed] Related Publications
The genetic status of candidate tumor suppressor genes (TSGs) at chromosome 3p has not yet been elucidated in intrahepatic cholangiocarcinoma (iCCA). Herein, we retrospectively investigated 32 fresh iCCA case samples from a single medical institution to clarify mutations of 11 TSGs by next-generation sequencing. Validation of the mutations was performed on the MassARRAY platform or by high-resolution melting curve analysis. We then integrated the gene mutations into copy number alterations at chromosome 3p that had been generated in a previous study using the same fresh iCCA samples, and correlated the integration results with the clinicopathologic features. Nine of the 32 (28.1%) iCCA patients had gene mutations at chromosome 3p, totaling 11 mutations across five genes. Those included five (15.6%) BAP1 mutations, two each (6.3%) of CACNA2D3 and RASSF1 mutations, and one each (3.1%) of ATG7 and PLCD1 mutations. Six (18.8%) cases had concurrent loss of chromosome 3p and gene mutations. Patients with TSG mutations had shorter disease-free and survival times than those without the mutations. Our data showed that iCCA patients with TSG mutations at chromosome 3p faced an adverse prognosis. BAP1 was the common target of mutational inactivation and may be a principal driver of 3p21 losses.

Couto PP, Bastos-Rodrigues L, Schayek H, et al.
Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.
Carcinogenesis. 2017; 38(11):1112-1118 [PubMed] Related Publications
Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.

Shao Q, Luo X, Yang D, et al.
Phospholipase Cδ1 suppresses cell migration and invasion of breast cancer cells by modulating KIF3A-mediated ERK1/2/β- catenin/MMP7 signalling.
Oncotarget. 2017; 8(17):29056-29066 [PubMed] Free Access to Full Article Related Publications
Phospholipase C δ1 (PLCD1) encodes an enzyme involved in energy metabolism, calcium homeostasis and intracellular movement. It is located at 3p22 in a region that is frequently deleted in multiple cancers, and the PLCD1 enzyme is a potential tumour suppressor in breast cancer that inhibits matrix metalloprotease (MMP) 7, but the detailed mechanism remains elusive. In this study, we found that PLCD1 was downregulated in breast cancers, and the gain-or-loss functional assay revealed that PLCD1 inhibited cell migration and invasion in vitro via the ERK1/2/β-catenin/MMP7 signalling pathway. Furthermore, KIF3A was identified as a downstream mediator of PLCD1, and there was an inverse correlation between the expression of PLCD1 and KIF3A. Knockdown of KIF3A expression alone suppressed cell migration and invasion, and attenuated ERK1/2/β-catenin/MMP7 signalling that was reactivated by knocking down PLCD1 in vitro. Collectively, our findings suggest that PLCD1 acts as a tumour suppressor, by KIF3A-mediated suppression of ERK1/2/β-catenin/MMP7 signalling, at least in part, in breast cancer.

Mu H, Wang N, Zhao L, et al.
Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer.
Exp Cell Res. 2015; 332(2):179-89 [PubMed] Related Publications
Our previous study showed that PLCD1 significantly decreases cell proliferation and affects cell cycle progression in breast cancer cells. In the present study, we aimed to investigate its functional and molecular mechanisms, and whether or not can become a new target for gene therapies. We found reduced PLCD1 protein expression in breast tumor tissues compared with paired surgical margin tissues. PLCD1 promoter CpG methylation was detected in 55 of 96 (57%) primary breast tumors, but not in surgical-margin tissues and normal breast tissues. Ectopic expression of PLCD1 inhibited breast tumor cell proliferation in vivo by inducing apoptosis and suppressed tumor cell migration by regulating cytoskeletal reorganization proteins including RhoA and phospho-cofilin. Furthermore, we found that PLCD1 induced p53 accumulation, increased p27 and p21 protein levels, and cleaved PARP. Finally, we constructed an adenoviral vector expressing PLCD1 (AdH5-PLCD1), which exhibited strong cytotoxicity in breast cancer cells. Our findings provide insights into the development of PLCD1 gene therapies for breast cancer and perhaps, other human cancers.

Song JJ, Liu Q, Li Y, et al.
Epigenetic inactivation of PLCD1 in chronic myeloid leukemia.
Int J Mol Med. 2012; 30(1):179-84 [PubMed] Related Publications
Phospholipase C δ1 (PLCD1), is located at the important tumor suppressor locus 3p22. It encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. PLCD1 has been studied in some human solid tumors relating to the CpG island methylation of the gene promoter as a functional tumor suppressor. However, no such information is available in chronic myeloid leukemia (CML). In this study, we investigated PLCD1 expression in the CML K562 cell line (0/1) and 15% (2/13) of bone marrow mononuclear cells with CML by using semi-quantitative PCR. The CpG island (CGI) methylation status of the PLCD1 promoter was detected in K562 (0/1) and 56% (23/41) of CML patients by methylation-specific PCR (MSP), but not in the normal adult bone marrow mononuclear cells. Furthermore, the DNA demethylation agent 5'-aza-2'deoxycytidine restored the expression of PLCD1 in K562 cells. Functional studies showed that ectopic expression of PLCD1 in K562 cells was able to dramatically inhibit their colony formation and induce cell cycle G1 arrest, suggesting that PLCD1 acts as a functional tumor suppressor and may serve as a biomarker for possible early detection and prognosis of CML.

Danielsen SA, Cekaite L, Ågesen TH, et al.
Phospholipase C isozymes are deregulated in colorectal cancer--insights gained from gene set enrichment analysis of the transcriptome.
PLoS One. 2011; 6(9):e24419 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the "Phosphatidylinositol signaling network", comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.

Xiang T, Li L, Fan Y, et al.
PLCD1 is a functional tumor suppressor inducing G(2)/M arrest and frequently methylated in breast cancer.
Cancer Biol Ther. 2010; 10(5):520-7 [PubMed] Related Publications
Chromosome 3p harbors multiple tumor-suppressor genes. PLCD1, located at 3p22, encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movement. We investigated the epigenetic alterations of PLCD1 and its tumor suppressor function in breast cancer. Frequent downregulation/silencing of PLCD1 was shown in most breast cancer cell lines by using semi-quantitative PCR. Promoter methylation of PLCD1 was detected in 78% (7/9) of cell lines and 52% (13/25) of primary tumors by Methylation-specific PCR (MSP), but not in any tumor adjacent breast tissues and normal breast tissues, which was further confirmed by bisulfite genomic sequencing (BGS). The silencing of PLCD1 could be reversed by pharmacological demethylation, indicating a methylation-mediated mechanism. Ectopic expression of PLCD1 in silenced breast cancer cells significantly inhibited their colony formation. In addition, PLCD1 inhibited tumor cell migration and induced cell cycle G(2)/M arrest. Thus, this study for the first time demonstrates the frequent inactivation of PLCD1 by promoter methylation and its tumor inhibitory function in breast cancer. Tumor-specific methylation of PLCD1 might serve as a biomarker for possible early detection and prognosis prediction of breast cancer.

Hu XT, Zhang FB, Fan YC, et al.
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.
Oncogene. 2009; 28(26):2466-75 [PubMed] Related Publications
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'-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.

Qin YR, Fu L, Sham PC, et al.
Single-nucleotide polymorphism-mass array reveals commonly deleted regions at 3p22 and 3p14.2 associate with poor clinical outcome in esophageal squamous cell carcinoma.
Int J Cancer. 2008; 123(4):826-30 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common solid tumors in the world with poor prognosis. Deletion of chromosome 3p is one of the most frequent chromosomal alterations in ESCC, suggesting the existence of one or more tumor suppressor genes (TSGs) at this region. In the present study, a recently developed high-throughput and high-resolution technology, single-nucleotide polymorphism (SNP)-mass array, was applied to investigate loss of heterozygosity on 3p in 100 primary ESCC cases with 386 SNP markers. Four commonly deleted regions (CDRs) at 3p26.3, 3p22, 3p21.3 and 3p14.2 were identified. Absent and down-regulated expression of several candidate TSGs, including CHL1, PCAF, RBMS3, PLCD1 and CACNA2D3, were detected in primary ESCC tumors and ESCC cell lines. Moreover, deletions of CDRs 2 and 4 were correlated with advanced tumor stage and deletion of CDR2 was associated with tumor metastasis in ESCC. Our findings provided evidence that minimal deleted regions at 3p26.3, 3p22, 3p21.3 and 3p14.2 containing potential TSGs may contribute to the pathogenesis of esophageal cancer.

Healy KD, Hodgson L, Kim TY, et al.
DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms.
Mol Carcinog. 2008; 47(5):326-37 [PubMed] Free Access to Full Article Related Publications
Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-delta1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC.

Ishikawa S, Takahashi T, Ogawa M, Nakamura Y
Genomic structure of the human PLCD1 (phospholipase C delta 1) locus on 3p22-->p21.3.
Cytogenet Cell Genet. 1997; 78(1):58-60 [PubMed] Related Publications
A large-scale sequencing analysis of genomic DNA in the vicinity of homozygous deletion on chromosome 3p found in a lung cancer cell line disclosed that the gene encoding phospholipase C delta 1 (PLCD1) is located just distal to the region removed by the deletion We report the genomic structure of this gene, which consists of 15 exons and spans about 22 kb, and its precise localization to chromosome 3p22-->p21.3.

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Cite this page: Cotterill SJ. PLCD1, Cancer Genetics Web: Accessed:

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