title: Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer.
abstract: 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.
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors: Haixi
authors: H
authors: Mu
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Na
authors: N
authors: Wang
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Lijuan
authors: L
authors: Zhao
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Shuman
authors: S
authors: Li
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Qianqian
authors: Q
authors: Li
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Ling
authors: L
authors: Chen
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Xinrong
authors: X
authors: Luo
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Zhu
authors: Z
authors: Qiu
authors: Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors: Lili
authors: L
authors: Li
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors: Guosheng
authors: G
authors: Ren
authors: Chongqing Health Service Center, Chongqing 400020, China.
authors: Yongzhu
authors: Y
authors: Xu
authors: The Wistar Institute, Philadelphia, PA, USA.
authors: Xiangyang
authors: X
authors: Zhou
authors: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: xiangtx1@gmail.com.
authors: Tingxiu
authors: T
authors: Xiang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D003599:Cytoskeleton / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D054803:Phospholipase C delta / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047368:Tumor Burden
chemical_list: C518024:PLCD1 protein, human; D054803:Phospholipase C delta; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7
keywords: Adenovirus; Breast cancer; Gene therapy; Methylation; PLCD1