The evolutionarily conserved Par3/Par6/aPKC complex regulates the polarity establishment of diverse cell types and distinct polarity-driven functions. However, how the Par complex is concentrated ...beneath the membrane to initiate cell polarization remains unclear. Here we show that the Par complex exhibits cell cycle-dependent condensation in Drosophila neuroblasts, driven by liquid-liquid phase separation. The open conformation of Par3 undergoes autonomous phase separation likely due to its NTD-mediated oligomerization. Par6, via C-terminal tail binding to Par3 PDZ3, can be enriched to Par3 condensates and in return dramatically promote Par3 phase separation. aPKC can also be concentrated to the Par3N/Par6 condensates as a client. Interestingly, activated aPKC can disperse the Par3/Par6 condensates via phosphorylation of Par3. Perturbations of Par3/Par6 phase separation impair the establishment of apical-basal polarity during neuroblast asymmetric divisions and lead to defective lineage development. We propose that phase separation may be a common mechanism for localized cortical condensation of cell polarity complexes.
Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)
. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality ...conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC
. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-Kras
; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
Metabolite sensing is one of the most fundamental biological processes. During evolution, multilayered mechanisms developed to sense fluctuations in a wide spectrum of metabolites, including ...nutrients, to coordinate cellular metabolism and biological networks. To date, AMPK and mTOR signaling are among the best-understood metabolite-sensing and signaling pathways. Here, we propose a sensor-transducer-effector model to describe known mechanisms of metabolite sensing and signaling. We define a metabolite sensor by its specificity, dynamicity, and functionality. We group the actions of metabolite sensing into three different modes: metabolite sensor-mediated signaling, metabolite-sensing module, and sensing by conjugating. With these modes of action, we provide a systematic view of how cells sense sugars, lipids, amino acids, and metabolic intermediates. In the future perspective, we suggest a systematic screen of metabolite-sensing macromolecules, high-throughput discovery of biomacromolecule-metabolite interactomes, and functional metabolomics to advance our knowledge of metabolite sensing and signaling. Most importantly, targeting metabolite sensing holds great promise in therapeutic intervention of metabolic diseases and in improving healthy aging.
Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies ...for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.
Sirtuins (SIRTs) are a class of lysine deacylases that regulate cellular metabolism and energy homeostasis. Although sirtuins have been proposed to function in nutrient sensing and signaling, the ...underlying mechanism remains elusive. SIRT7, a histone H3K18‐specific deacetylase, epigenetically controls mitochondria biogenesis, ribosomal biosynthesis, and DNA repair. Here, we report that SIRT7 is methylated at arginine 388 (R388), which inhibits its H3K18 deacetylase activity. Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo. R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization. PRMT6‐induced H3K18 hyperacetylation at SIRT7‐target gene promoter epigenetically promotes mitochondria biogenesis and maintains mitochondria respiration. Moreover, high glucose enhances R388 methylation in mouse fibroblasts and liver tissue. PRMT6 signals glucose availability to SIRT7 in an AMPK‐dependent manner. AMPK induces R388 hypomethylation by disrupting the association between PRMT6 and SIRT7. Together, PRMT6‐induced arginine methylation of SIRT7 coordinates glucose availability with mitochondria biogenesis to maintain energy homeostasis. Our study uncovers the regulatory role of SIRT7 arginine methylation in glucose sensing and mitochondria biogenesis.
Synopsis
PRMT6 methylates and thereby inhibits SIRT7, which epigenetically promotes mitochondria biogenesis and connects it to glucose availability in an AMPK‐dependent manner.
PRMT6 methylates SIRT7 at R388 to suppress its H3K18 deacetylase activity.
PRMT6 modulates SIRT7 methylation in an AMPK‐dependent manner.
SIRT7 methylation connects glucose sensing with mitochondria biogenesis.
PRMT6 methylates and thereby inhibits SIRT7, which epigenetically promotes mitochondria biogenesis and connects it to glucose availability in an AMPK‐dependent manner.
The control of organ size is a basic biological question. In the past several years, the Hippo signaling pathway has been delineated and shown to be crucial in control of organ size in both ...Drosophila and mammals. Acting downstream of the Hippo pathway is the Yki/YAP/TAZ transcription co-activators. In mammalian cells, the Hippo pathway kinase cascade inhibits YAP and its paralog TAZ by phosphorylation and promotion of their cytoplasmic localization. The TEAD family transcription factors have recently been identified as evolutionarily conserved key mediators of YAP biological functions. yap is a candidate oncogene, and several other components of the Hippo pathway are tumor suppressors. Dysregulation of the Hippo pathway contributes to the loss of contact inhibition observed in cancer cells. Therefore, the Hippo–YAP pathway connects the regulation of organ size and tumorigenesis.
Glycolytic enzyme phosphoglycerate mutase (PGAM) plays an important role in coordinating energy production with generation of reducing power and the biosynthesis of nucleotide precursors and amino ...acids. Inhibition of PGAM by small RNAi or small molecule attenuates cell proliferation and tumor growth. PGAM activity is commonly upregulated in tumor cells, but how PGAM activity is regulated in vivo remains poorly understood. Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. Increased levels of reactive oxygen species stimulate PGAM2 deacetylation and activity by promoting its interaction with SIRT2. Substitution of endogenous PGAM2 with an acetylation mimetic mutant K100Q reduces cellular NADPH production and inhibits cell proliferation and tumor growth. These results reveal a mechanism of PGAM2 regulation and NADPH homeostasis in response to oxidative stress that impacts cell proliferation and tumor growth.
Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and ...inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.
•Acetylation stabilizes ACLY•Lung cancer has increased ACLY acetylation
Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer‐induced metabolic ...changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. Recent advances in cancer metabolism shed light on how aberrations in metabolites and metabolic enzymes modify epigenetic programs. The metabolism‐induced recoding of epigenetics in cancer depends strongly on nutrient availability for tumor cells. In this review, we focus on metabolic remodeling of epigenetics in cancer and examine potential mechanisms by which cancer cells integrate nutritional inputs into epigenetic modification.
Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and ...is important for cell growth. Elevated transcription by c-Myc or HIF1α may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.
► Acetylation inhibits LDH-A activity ► Acetylation targets LDH-A for chaperone-mediated autophagy ► SIRT2 regulates LDH-A acetylation ► Pancreatic cancer has decreased acetylation and increased protein levels of LDH-A
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