ABSTRACT
Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Cycle Proteins/physiology , Intracellular Signaling Peptides and Proteins/physiology , Sphingolipids/metabolism , Alkaline Ceramidase/physiology , Animals , Biopsy , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Lysophospholipids/physiology , Mice , Mice, Nude , Mitochondria/drug effects , Sp1 Transcription Factor/physiology , Sphingosine/analogs & derivatives , Sphingosine/physiology , Xenograft Model Antitumor AssaysABSTRACT
Sphingolipids have been implicated in mammalian placental development and function, but their regulation in the placenta remains unclear. Herein we report that alkaline ceramidase 2 (ACER2) plays a key role in sustaining the integrity of the placental vasculature by regulating the homeostasis of sphingolipids in mice. The mouse alkaline ceramidase 2 gene (Acer2) is highly expressed in the placenta between embryonic day (E) 9.5 and E12.5. Acer2 deficiency in both the mother and fetus decreases the placental levels of sphingolipids, including sphingoid bases (sphingosine and dihydrosphingosine) and sphingoid base-1-phosphates (sphingosine-1-phosphate and dihydrosphingosine-1-phosphate) and results in the in utero death of ≈50% of embryos at E12.5 whereas Acer2 deficiency in either the mother or fetus has no such effects. Acer2 deficiency causes hemorrhages from the maternal vasculature in the junctional and/or labyrinthine zones in E12.5 placentas. Moreover, hemorrhagic but not non-hemorrhagic Acer2-deficient placentas exhibit an expansion of parietal trophoblast giant cells with a concomitant decrease in the area of the fetal blood vessel network in the labyrinthine zone, suggesting that Acer2 deficiency results in embryonic lethality due to the atrophy of the fetal blood vessel network in the placenta. Taken together, these results suggest that ACER2 sustains the integrity of the placental vasculature by controlling the homeostasis of sphingolipids in mice.
Subject(s)
Alkaline Ceramidase/physiology , Hemorrhage/pathology , Lysophospholipids/metabolism , Placenta/pathology , Sphingolipids/metabolism , Sphingosine/analogs & derivatives , Vascular Diseases/pathology , Animals , Female , Hemorrhage/etiology , Hemorrhage/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Placenta/metabolism , Pregnancy , Sphingosine/metabolism , Vascular Diseases/etiology , Vascular Diseases/metabolismABSTRACT
Sphingolipids, a class of bioactive lipids found in cell membranes, can modulate the biophysical properties of the membranes and play a critical role in signal transduction. Sphingolipids are involved in autophagy in humans and yeast, but their role in autophagy in plants is not well understood. In this study, we reported that the AtACER, an alkaline ceramidase that hydrolyses ceramide to long-chain base (LCB), functions in autophagy process in Arabidopsis. Our empirical data showed that the loss of AtACER inhibited autophagy, and its overexpression promoted autophagy under nutrient, salinity, and oxidative stresses. Interestingly, nitrogen deprivation significantly affected the sphingolipid's profile in Arabidopsis thaliana, especially the LCBs. Furthermore, the exogenous application of LCBs also induced autophagy. Our findings revealed a novel function of AtACER, where it was found to involve in the autophagy process, thus, playing a crucial role in the maintenance of a dynamic loop between sphingolipids and autophagy for cellular homeostasis under various environmental stresses.
