LACTB is a tumour suppressor that modulates lipid metabolism and cell state

Zuzana Keckesova (), Joana Liu Donaher, Jasmine De Cock, Elizaveta Freinkman, Susanne Lingrell, Daniel A. Bachovchin, Brian Bierie, Verena Tischler, Aurelia Noske, Marian C. Okondo, Ferenc Reinhardt, Prathapan Thiru, Todd R. Golub, Jean E. Vance and Robert A. Weinberg ()
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Zuzana Keckesova: Whitehead Institute for Biomedical Research
Joana Liu Donaher: Whitehead Institute for Biomedical Research
Jasmine De Cock: Whitehead Institute for Biomedical Research
Elizaveta Freinkman: Whitehead Institute for Biomedical Research
Susanne Lingrell: University of Alberta
Daniel A. Bachovchin: Broad Institute, Massachusetts Institute of Technology
Brian Bierie: Whitehead Institute for Biomedical Research
Verena Tischler: Institute of Surgical Pathology, University Hospital Zurich
Aurelia Noske: Institute of Surgical Pathology, University Hospital Zurich
Marian C. Okondo: Chemical Biology Program, Memorial Sloan Kettering Cancer Center
Ferenc Reinhardt: Whitehead Institute for Biomedical Research
Prathapan Thiru: Whitehead Institute for Biomedical Research
Todd R. Golub: Broad Institute, Massachusetts Institute of Technology
Jean E. Vance: University of Alberta
Robert A. Weinberg: Whitehead Institute for Biomedical Research

Nature, 2017, vol. 543, issue 7647, 681-686

Abstract: Abstract Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.

Date: 2017
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DOI: 10.1038/nature21408

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