Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer

Wenwen Xue,Wuhao Li,Lin Zhou,Ying Yu,Qiang Xu,Jian Gao,Yixuan Wang,Yan Shen,Chengfei Jiang,Xin Li

doi:10.1038/s41392-021-00856-1

Abstract

Loss-of-function mutations frequently occur in tumor suppressor genes, i.e., p53, during the malignant progression of various cancers. Whether any intrinsic suppressor carries a rare mutation is largely unknown. Here, we demonstrate that intracellular cytokine-like protein 1 (CYTL1) plays a key role in preventing the robust glycolytic switching characteristic of breast cancer. A low intracellular CYTL1 level, not its mutation, is required for metabolic reprogramming. Breast cancer cells expressing an intracellular form of CYTL1 lacking a 1-22 aa signal peptide, ΔCYTL1, show significantly attenuated glucose uptake and lactate production, which is linked to the inhibition of cell growth and metastasis in vitro and in vivo. Mechanistically, CYTL1 competitively binds the N-terminal sequence of NDUFV1 to block MDM2-mediated degradation by the proteasome, leading to the stability of the NDUFV1 protein. In addition to inducing increased NAD+ levels, NDUFV1 interacts with Src to attenuate LDHA phosphorylation at tyrosine 10 and reduce lactate production. Our results reveal, for the first time, that CYTL1 is a novel tumor suppressor. Its function in reversing metabolic reprogramming toward glycolysis may be very important for the development of novel antitumor strategies.

Highlights

An outstanding feature of cancer cell metabolism is the ability to switch from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis, even when sufficient oxygen is present.[1]
Low intracellular Cytokine-like protein 1 (CYTL1) levels are required for metabolic reprogramming toward glycolysis in breast cancer cells To examine whether there is any novel tumor suppressor that is different from those currently known, we first performed bioinformatics analysis
Expression was significantly lower in tumor tissues than in adjacent nontumor tissues in breast cancer patients based on data obtained from The Cancer Genome Atlas (TCGA) database (Fig. 1a)

Summary

Introduction

An outstanding feature of cancer cell metabolism is the ability to switch from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis, even when sufficient oxygen is present.[1]. Tumor cells reduce the intracellular level of CYTL1, which has been shown to have a negative correlation with malignant progression in patients with breast cancer.

Results

Conclusion