title: Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.
abstract: 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.
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuhisa
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Soshi
authors.initials: S
authors.lastname: Kanemoto
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Asada
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Hino
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takai
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Department of Clinical Oncology and Neuro-oncology Program, Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurisu
authors.affiliation: Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D003470:Culture Media / Q000737:chemistry; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C518609:CREB3L2 protein, human; D003470:Culture Media; D053823:Hedgehog Proteins