title: Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells.
abstract: The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apcmin/+mouse model of intestinal tumorigenesis. Mechanistic investigations revealed that genetic and pharmacologic targeting of PLD1 promote the E2F1-dependent apoptotic program via both miR-192/4465-mediated downregulation of RB1 and inhibition of Akt-TopBP1 pathways. Moreover, the miRNA-RB1 axis and Akt pathway also contributed to the PLD1-mediated self-renewal capacity of colon cancer-initiating cells. Finally, PLD1-driven E2F1 target gene expression positively correlated with tumor stage in patients with colorectal cancer. Overall, our findings suggest that PLD1 mediates cross-talk between multiple major signaling pathways to promote the survival and malignancy of colon cancer cells and may therefore represent an ideal signaling node for therapeutic targeting. Cancer Res; 77(1); 142-52. ©2016 AACR.
authors: Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors: Dong Woo
authors: DW
authors: Kang
authors: Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Shin Wha
authors: SW
authors: Lee
authors: Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors: Won Chan
authors: WC
authors: Hwang
authors: Department of Statistics, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors: Bo Hui
authors: BH
authors: Lee
authors: Department of Statistics, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors: Yong-Seok
authors: YS
authors: Choi
authors: Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Young-Ah
authors: YA
authors: Suh
authors: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors: Kang-Yell
authors: KY
authors: Choi
authors: Department of Molecular Biology, Pusan National University, Busan, Republic of Korea. minds@pusan.ac.kr.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.|Genetic Engineering Institute, Pusan National University, Busan, Republic of Korea.
authors: Do Sik
authors: DS
authors: Min
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010739:Phospholipase D / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C110513:TOPBP1 protein, human; C492846:Topbp1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010739:Phospholipase D; C106801:phospholipase D1