Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7

• Published in: PloS one Vol. 10; no. 5; p. e0125982
• Main Authors: Iwamoto, Hideo, Matsuhisa, Koji, Saito, Atsushi, Kanemoto, Soshi, Asada, Rie, Hino, Kenta, Takai, Tomoko, Cui, Min, Cui, Xiang, Kaneko, Masayuki, Arihiro, Koji, Sugiyama, Kazuhiko, Kurisu, Kaoru, Matsubara, Akio, Imaizumi, Kazunori
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.05.2015; Public Library of Science (PLoS)
• Subjects: Antineoplastic drugs; Antitumor agents; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - secretion; Biochemistry; C-Terminus; Cancer; Cancer cells; Cell activation; Cell culture; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Culture media; Culture Media - chemistry; Drug development; Drugs; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Gene expression; Genetic aspects; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Health sciences; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Hypoxia; Kinases; Leucine; Leucine zipper proteins; Ligands; Mammals; Medical prognosis; Mutation; N-Terminus; Nuclei; Oxidative stress; Phosphorylation; Physiological aspects; Protein folding; Proteolysis; Signal Transduction; Signaling; Tissues; Transcription activation; Transcription factors; Tumor cell lines; Urology; Japan
• DOI: 10.1371/journal.pone.0125982
• ISSN: 1932-6203

BBF2H7 is an endoplasmic reticulum (ER)-resident transmembrane basic leucine zipper (bZIP) transcription factor that is cleaved at the transmembrane domain by regulated intramembrane proteolysis in response to ER stress. The cleaved cytoplasmic N-terminus containing transcription activation and bZIP domains translocates into the nucleus to promote the expression of target genes. In chondrocytes, the cleaved luminal C-terminus is extracellularly secreted and facilitates proliferation of neighboring cells through activation of Hedgehog signaling. In the present study, we found that Bbf2h7 expression levels significantly increased by 1.070-2.567-fold in several tumor types including glioblastoma compared with those in respective normal tissues, using the ONCOMINE Cancer Profiling Database. In some Hedgehog ligand-dependent cancer cell lines including glioblastoma U251MG cells, the BBF2H7 C-terminus was secreted from cells into the culture media and promoted cancer cell proliferation through activation of Hedgehog signaling. Knockdown of Bbf2h7 expression suppressed the proliferation of U251MG cells by downregulating Hedgehog signaling. The impaired cell proliferation and Hedgehog signaling were recovered by addition of BBF2H7 C-terminus to the culture medium of Bbf2h7-knockdown U251MG cells. These data suggest that the secreted luminal BBF2H7 C-terminus is involved in Hedgehog ligand-dependent cancer cell proliferation through activation of Hedgehog signaling. Thus, the BBF2H7 C-terminus may be a novel target for the development of anticancer drugs.