title: The ERK signaling target RNF126 regulates anoikis resistance in cancer cells by changing the mitochondrial metabolic flux.
abstract: Loss of anchorage to the extracellular matrix leads to apoptosis (anoikis) in normal cells, but cancerous cells are usually resistant to such stress. Here we report the pivotal role of an E3 ubiquitin ligase, ring-finger protein 126 (RNF126), in the resistance of cancer cells to the stress associated with non-adherent conditions. Non-adherent cancer cells exhibited increased flux through the tricarboxylic acid cycle via increased conversion of pyruvate to acetyl-CoA. RNF126 was found to act as a ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), resulting in their proteasomal degradation. This decrease in PDK levels allowed pyruvate dehydrogenases to catalyze the conversion of pyruvate to acetyl-CoA. Moreover, depletion of RNF126 or increased expression of PDK1 in cancer cells suppressed colony formation in soft agar as well as tumorigenicity in mice. RNF126 expression in cancer cells was found to be under the control of the extracellular signal-regulated kinase signaling pathway, which is essential for anoikis resistance. Thus, RNF126 is an attractive molecule for treating cancer by selectively targeting anchorage-independent growth.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Yoshino
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki J
authors.initials: HJ
authors.lastname: Nakaoka
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Kanamori
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Sakamoto
keywords: PDK; RNF126; anoikis; cancer; metabolism; ubiquitination