MiR-378 mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway

Lillian J. Eichner; Marie Claude Perry; Catherine R. Dufour; Nicholas Bertos; Morag Park; Julie St-Pierre; Vincent Giguere

doi:10.1016/j.cmet.2010.09.002

MiR-378 mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway

Lillian J. Eichner, Marie Claude Perry, Catherine R. Dufour, Nicholas Bertos, Morag Park, Julie St-Pierre, Vincent Giguere^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

256 Scopus citations

Abstract

Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378 is embedded within PPARGC1b which encodes PGC-1β, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378 expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378 performs this function by inhibiting the expression of two PGC-1β partners, ERRγ and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378 expression correlates with progression of human breast cancer. These results identify miR-378 as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.

Original language	English (US)
Pages (from-to)	352-361
Number of pages	10
Journal	Cell Metabolism
Volume	12
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2010.09.002
State	Published - Oct 6 2010
Externally published	Yes

Funding

We thank T. Duchaine for helpful discussion and critical reading of the manuscript; W. Muller for the NMuMG and NT2196 cell lines; A. Dydensborg for guidance with the MitoTracker experiments; and V. Chenard, J.A. Bader, and M. Souleimanova for technical assistance. We thank R.M. Evans (Salk Institute) for the Ppargc1b knockout mice. L.J.E. is a recipient of studentships from the McGill University Health Centre Research Institute and the Fonds de la Recherche en Sant\u00E9 du Qu\u00E9bec (FRSQ). M.-C.P. is a recipient of a studentship from the National Science and Engineering Research Council of Canada. V.G. and J.St-P. are supported by the Canadian Institutes for Health Research (grants MOP-64275, MOP-77763, MOP-84227, and IC1-102947). M.P., J.St-P., and V.G. are supported by an institutional grant from the FRSQ to the Morris and Rosalind Goodman Cancer Research Centre. This work was also supported by grants from the Qu\u00E9bec Breast Cancer Foundation (QBCF) and the Banque de tissu et de donn\u00E9es of the R\u00E9seau de la recherche sur le cancer (RRCancer) of the FRSQ (to M.P.), and a Program Project grant from the Canadian Cancer Society Research Institute/Terry Fox Foundation (to M.P. and V.G.). M.P. holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2010.09.002

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title = "MiR-378 mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway",

abstract = "Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378 is embedded within PPARGC1b which encodes PGC-1β, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378 expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378 performs this function by inhibiting the expression of two PGC-1β partners, ERRγ and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378 expression correlates with progression of human breast cancer. These results identify miR-378 as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.",

author = "Eichner, {Lillian J.} and Perry, {Marie Claude} and Dufour, {Catherine R.} and Nicholas Bertos and Morag Park and Julie St-Pierre and Vincent Giguere",

note = "Funding Information: We thank T. Duchaine for helpful discussion and critical reading of the manuscript; W. Muller for the NMuMG and NT2196 cell lines; A. Dydensborg for guidance with the MitoTracker experiments; and V. Chenard, J.A. Bader, and M. Souleimanova for technical assistance. We thank R.M. Evans (Salk Institute) for the Ppargc1b knockout mice. L.J.E. is a recipient of studentships from the McGill University Health Centre Research Institute and the Fonds de la Recherche en Sant{\'e} du Qu{\'e}bec (FRSQ). M.-C.P. is a recipient of a studentship from the National Science and Engineering Research Council of Canada. V.G. and J.St-P. are supported by the Canadian Institutes for Health Research (grants MOP-64275, MOP-77763, MOP-84227, and IC1-102947). M.P., J.St-P., and V.G. are supported by an institutional grant from the FRSQ to the Morris and Rosalind Goodman Cancer Research Centre. This work was also supported by grants from the Qu{\'e}bec Breast Cancer Foundation (QBCF) and the Banque de tissu et de donn{\'e}es of the R{\'e}seau de la recherche sur le cancer (RRCancer) of the FRSQ (to M.P.), and a Program Project grant from the Canadian Cancer Society Research Institute/Terry Fox Foundation (to M.P. and V.G.). M.P. holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University. ",

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AU - Eichner, Lillian J.

AU - Perry, Marie Claude

AU - Dufour, Catherine R.

AU - Bertos, Nicholas

AU - Park, Morag

AU - St-Pierre, Julie

AU - Giguere, Vincent

N1 - Funding Information: We thank T. Duchaine for helpful discussion and critical reading of the manuscript; W. Muller for the NMuMG and NT2196 cell lines; A. Dydensborg for guidance with the MitoTracker experiments; and V. Chenard, J.A. Bader, and M. Souleimanova for technical assistance. We thank R.M. Evans (Salk Institute) for the Ppargc1b knockout mice. L.J.E. is a recipient of studentships from the McGill University Health Centre Research Institute and the Fonds de la Recherche en Santé du Québec (FRSQ). M.-C.P. is a recipient of a studentship from the National Science and Engineering Research Council of Canada. V.G. and J.St-P. are supported by the Canadian Institutes for Health Research (grants MOP-64275, MOP-77763, MOP-84227, and IC1-102947). M.P., J.St-P., and V.G. are supported by an institutional grant from the FRSQ to the Morris and Rosalind Goodman Cancer Research Centre. This work was also supported by grants from the Québec Breast Cancer Foundation (QBCF) and the Banque de tissu et de données of the Réseau de la recherche sur le cancer (RRCancer) of the FRSQ (to M.P.), and a Program Project grant from the Canadian Cancer Society Research Institute/Terry Fox Foundation (to M.P. and V.G.). M.P. holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University.

PY - 2010/10/6

Y1 - 2010/10/6

N2 - Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378 is embedded within PPARGC1b which encodes PGC-1β, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378 expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378 performs this function by inhibiting the expression of two PGC-1β partners, ERRγ and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378 expression correlates with progression of human breast cancer. These results identify miR-378 as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.

AB - Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378 is embedded within PPARGC1b which encodes PGC-1β, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378 expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378 performs this function by inhibiting the expression of two PGC-1β partners, ERRγ and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378 expression correlates with progression of human breast cancer. These results identify miR-378 as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.

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JF - Cell Metabolism

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ER -

MiR-378 mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway

Abstract

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UN SDGs

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