C/EBP\u03b2-LIP induces cancer-type metabolic reprogramming by regulating the let-7/LIN28B circuit in mice

Tobias Ackermann,Britt A Sterken,Marco Groth,Götz Hartleben,Sara R Krauss,Guido Mastrobuoni,Cornelis F Calkhoven,Hidde R Zuidhof,Christine Müller,Mohamad A Zaini,Sameh A Youssef,Zhao-Qi Wang,Gerald De Haan,Alain De Bruin,Stefan Kempa,Gertrud Kortman,Matthias Platzer

doi:10.1038/s42003-019-0461-z

Abstract

The transcription factors LAP1, LAP2 and LIP are derived from the Cebpb-mRNA through the use of alternative start codons. High LIP expression has been associated with human cancer and increased cancer incidence in mice. However, how LIP contributes to cellular transformation is poorly understood. Here we present that LIP induces aerobic glycolysis and mitochondrial respiration reminiscent of cancer metabolism. We show that LIP-induced metabolic programming is dependent on the RNA-binding protein LIN28B, a translational regulator of glycolytic and mitochondrial enzymes with known oncogenic function. LIP activates LIN28B through repression of the let-7 microRNA family that targets the Lin28b-mRNA. Transgenic mice overexpressing LIP have reduced levels of let-7 and increased LIN28B expression, which is associated with metabolic reprogramming as shown in primary bone marrow cells, and with hyperplasia in the skin. This study establishes LIP as an inducer of cancer-type metabolic reprogramming and as a regulator of the let-7/LIN28B regulatory circuit.

Highlights

The transcription factors LAP1, LAP2 and LIP are derived from the Cebpb-mRNA through the use of alternative start codons
To examine LIP-dependent cellular metabolism we measured the extracellular acidification rate (ECAR) as an indicator for glycolytic flux and the oxygen consumption rate (OCR) as a measure for mitochondrial respiration using the Seahorse XF96 analyser in wild-type mouse embryonic fibroblasts (MEFs) versus MEFs derived from C/EBPβΔuORF mice that express lower LIP/LAP ratios compared to wt due to deficient endogenous LIP production[23,24,34] (Fig. 1a and Supplementary Fig. 1a)
Basal ECAR, maximal ECAR and basal OCR, but not maximal OCR, were decreased in C/EBPβΔuORF MEFs compared to wt MEFs (Fig. 1b)

Summary

Introduction

The transcription factors LAP1, LAP2 and LIP are derived from the Cebpb-mRNA through the use of alternative start codons. We show that LIP-induced metabolic programming is dependent on the RNA-binding protein LIN28B, a translational regulator of glycolytic and mitochondrial enzymes with known oncogenic function. Transgenic mice overexpressing LIP have reduced levels of let-7 and increased LIN28B expression, which is associated with metabolic reprogramming as shown in primary bone marrow cells, and with hyperplasia in the skin. This study establishes LIP as an inducer of cancer-type metabolic reprogramming and as a regulator of the let-7/LIN28B regulatory circuit. As RNA-binding proteins, LIN28A/B stimulate the translation of several glycolytic and mitochondrial enzymes in the context of cell metabolism, tissue repair and cancer[4,5,6,7]. The studies demonstrate that LIP has oncogenic capacities, but whether and how metabolic functions of LIP are involved is not known

Methods

Results

Conclusion