Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been ...largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.
Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that functions mainly in the nucleus and cytoplasm. However, whether SND1 regulates ...cellular activity through mitochondrial-related functions remains unclear. Herein, we demonstrate that SND1 is localized to mitochondria to promote phosphoglycerate mutase 5 (PGAM5)-mediated mitophagy. We find that SND1 is present in mitochondria based on mass spectrometry data and verified this phenomenon in different liver cancer cell types by performing organelle subcellular isolation. Specifically, The N-terminal amino acids 1-63 of SND1 serve as a mitochondrial targeting sequence (MTS), and the translocase of outer membrane 70 (TOM 70) promotes the import of SND1 into mitochondria. By immunoprecipitation-mass spectrometry (IP-MS), we find that SND1 interacts with PGAM5 in mitochondria and is crucial for the binding of PGAM5 to dynamin-related protein 1 (DRP1). Importantly, we demonstrate that PGAM5 and SND1-MTS are required for SND1-mediated mitophagy under FCCP and glucose deprivation treatment as well as for SND1-mediated cell proliferation and tumor growth both
and
. Aberrant expression of SND1 and PGAM5 predicts poor outcomes in hepatocellular carcinoma (HCC) patients. Taken together, these findings establish a previously unappreciated role of SND1 and the association of mitochondrion-localized SND1 with PGAM5 in mitophagy and tumor progression.
It is known that tumor cells adapt characteristic metabolic phenotypes during cancer initiation and progression. The hallmark of tumor metabolism is aerobic glycolysis, or Warburg Effect, which was ...first described more than 80 years ago. Unlike normal cells, most cancer cells produce energy by a high rate of glycolic catabolism to lactate in the cytosol, rather than by oxidation of pyruvate in mitochondria, even in the presence of oxygen. Progress over the past decade has revealed that alterations of oncogenes and tumor suppressors are responsible for such metabolic reprogramming in cancer cells, however, the underlying molecular basis remains largely unknown. Mounting evidence shows the interplay between microRNAs and oncogenes/tumor suppressors, via key metabolic enzyme effecters, which could facilitate the Warburg Effect in cancer cells. In this review, we will summarize our current understanding of the roles of microRNAs, in particular their interplay with oncogenes/tumor suppressors such as cMyc, HIF-1 and P53, in tumor metabolism.
Background
Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ...ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.
Methods
Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription‐PCR (qRT‐PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP‐response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys‐Asp‐Glu‐Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer‐bearing mouse model was employed to analyze the effect of the HDAC3‐KDELR2 axis on tumor growth.
Results
KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT‐PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3‐KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3‐KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.
Conclusion
Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi‐the endoplasmic reticulum traffic transport protein to HDAC‐controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.
While metabolic reprogramming of cancer cells has long been considered from the standpoint of how and why cancer cells preferentially utilize glucose via aerobic glycolysis, the so-called Warburg ...Effect, the progress in the following areas during the past several years has substantially advanced our understanding of the rewired metabolic network in cancer cells that is intertwined with oncogenic signaling. First, in addition to the major nutrient substrates glucose and glutamine, cancer cells have been discovered to utilize a variety of unconventional nutrient sources for survival. Second, the deregulated biomass synthesis is intertwined with cell cycle progression to coordinate the accelerated progression of cancer cells. Third, the reciprocal regulation of cancer cell's metabolic alterations and the microenvironment, involving extensive host immune cells and microbiota, have come into view as critical mechanisms to regulate cancer progression. These and other advances are shaping the current and future paradigm of cancer metabolism.
Nature Communications 8: Article number: 15278 (2017); Published 5 May 2017; Updated 30 March 2018 The originally published version of this Article contained errors in Fig. 6. In panel l, the Nile ...Red and Merge images of cells treated with shMYC were inadvertently duplicated from the equivalent images of cells treated with MEN1-sh1 and MEN-sh2 in panel n of the same figure.
HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer ...therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (Actino
actoMycin
, a compound extracted from metabolites of
, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of
which shows promising anti-cancer potential.
Since the description of the Warburg effect 90 years ago, metabolic reprogramming has been gradually recognized as a major hallmark of cancer cells. Mounting evidence now indicates that cancer is a ...kind of metabolic disease, quite distinct from conventional perception. While metabolic alterations in cancer cells have been extensively observed in glucose, lipid, and amino acid metabolisms, its underlying regulatory mechanisms are still poorly understood. Noncoding RNA, also known as the "dark matter in life," functions through various mechanisms at RNA level regulating different biological pathways. The last two decades have witnessed the booming of noncoding RNA study on microRNA (miRNA), long noncoding RNA (lncRNA), circular RNA (circRNA), PIWI-interacting RNA (piRNA), etc. In this chapter, we will discuss the regulatory roles of noncoding RNAs on cancer metabolism.
Adenosine 5'‐monophosphate (AMP)‐activated protein kinase (AMPK) is an important cellular metabolite‐sensing enzyme that can directly sense changes not only in ATP but also in metabolites associated ...with carbohydrates and fatty acids. However, less is known about whether and how AMPK senses variations in cellular amino acids. Here, we show that cysteine deficiency significantly triggers calcium/calmodulin‐dependent protein kinase kinase 2 (CaMKK2)‐mediated activation of AMPK. In addition, we found that CaMKK2 directly associates with cysteinyl‐tRNA synthetase (CARS), which then binds to AMPKγ2 under cysteine deficiency to activate AMPK. Interestingly, we discovered that cysteine inhibits the binding of CARS to AMPKγ2, and thus, under cysteine deficiency conditions wherein the inhibitory effect of cysteine is abrogated, CARS mediates the binding of AMPK to CaMKK2, resulting in the phosphorylation and activation of AMPK by CaMKK2. Importantly, we demonstrate that blocking AMPK activation leads to cell death under cysteine‐deficient conditions. In summary, our study is the first to show that CARS senses the absence of cysteine and activates AMPK through the cysteine–CARS–CaMKK2–AMPKγ2 axis, a novel adaptation strategy for cell survival under nutrient deprivation conditions.
Synopsis
Whether metabolite‐sensing enzyme AMPK regulates cell survival upon amino acid starvation, remains unclear. This study identifies the cysteine‐specific tRNA synthetase (CARS) as an activator of CaMKK2‐dependent AMPK signalling, revealing a novel cellular pathway for adapting to nutrient deprivation.
Cysteine inhibits CaMKK2‐dependent activation of AMPK in human cancer cell lines.
Cysteine depletion triggers binding of CARS to CaMKK2 and AMPKγ2, promoting AMPK phosphorylation at T172.
The CARS‐CaMKK2‐AMPK axis promotes cell survival under cysteine‐deficient conditions.
AMP‐activated protein kinase AMPK senses low amino acid levels through a cysteine‐CARS‐CaMKK2‐AMPKγ2 axis.
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