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

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.

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma

“…It was identified as a tumor suppressor in lung cancer via inhibiting the tumor invasion and metastasis rather proliferation (72). While a similar effect on tumor growth and metastasis was achieved via inhibition of metabolic reprogramming in breast cancer cells expressing an intracellular form of CYTL1 that lacked a 1-22 aa signal peptide, DCYTL1 (73). In contrast, CYTL1 was involved in the Frontiers in Immunology frontiersin.org growth and metastasis of neuroblastoma cells (74).…”

Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer

“…The loss and mutation of tumor-suppressor genes are the main reason for tumor progression and clinical resistance to various therapeutic methods 40,41 . Reversal of the phenotype induced by loss or mutation of tumor suppressors has been proven to be an elusive goal 42,43 .…”

Cytokine‐Like Protein 1 (CYTL1) as a Key Target of M‐Stage Immune Infiltration in Stomach Adenocarcinoma

“…In previous studies [ 21 , 22 ], CYTL1 was shown to be involved in cartilage formation and inhibited inflammation. In addition, Xue et al [ 9 ] stated that CYTL1 acts as a tumor suppressor and maintains intracellular metabolic homeostasis in tumors, although Wang et al [ 14 ] initially explored the expression patterns of CYTL1 in breast, prostate, lung, and gastric cancers through bioinformatics. However, no further research has been conducted to confirm the mechanism of CYTL1 in STAD.…”

“…Cytokine-like protein 1 (CYTL1) [ 9 ], also known as C17, is a 136-amino acid protein secreted by CD34 hematopoietic cells. CYTL1 is closely related to inflammation [ 10 , 11 ], is highly expressed in cartilage tissue [ 12 ], prevents inflammatory arthritis and joint destruction, and inhibits the expression of inflammation-related factors.…”