Arginine methylation of PPP1CA by CARM1 regulates glucose metabolism and affects osteogenic differentiation and osteoclastic differentiation

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(9)

Published: Aug. 30, 2023

The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation fusion are driven by oxidative phosphorylation.By polymerase chain reaction as well Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, mouse precranial osteoblast cell line MC3T3-E1 monocyte macrophage leukaemia RAW264.7, related genes during osteogenic differentiation. Using gene overexpression (lentivirus) loss-of-function approach (CRISPR/Cas9-mediated knockout) vitro, examined whether CARM1 regulates regulation. Transcriptomic assays metabolomic were used find mechanism action CARM1. Furthermore, vitro methylation applied clarify site PPP1CA CARM1.We discovered that reprogrammed glucose metabolism from phosphorylation glycolysis, thereby promoting inhibiting osteoclastic In vivo experiments revealed significantly decreased loss osteoporosis model mice. Mechanistically, methylated R23 PPP1CA, affected dephosphorylation AKT-T450 AMPK-T172, increased activities phosphofructokinase-1 pructose-2,6-biphosphatase3, causing an up-regulation glycolytic flux. At same time, a transcriptional coactivator, regulated pyruvate dehydrogenase kinase 3, which resulted inhibition activity tricarboxylic acid cycle, leading subsequent decrease flux phosphorylation.These findings reveal for first time affects both osteogenesis through regulation, represent new feasible treatment strategy

Language: Английский

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CARM1 arginine methyltransferase as a therapeutic target for cancer

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(9), P. 105124 - 105124

Published: Aug. 1, 2023

Coactivator-associated arginine methyltransferase 1 (CARM1) is an that posttranslationally modifies proteins regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators transcription, splicing factors. CARM1 overexpressed in many different cancer types, often promotes factor programs are co-opted as drivers the transformed cell state, a process known addiction. Targeting these oncogenic pathways difficult but could be addressed by removing activity key coactivators on which they rely. ubiquitously expressed, its KO less detrimental embryonic development than deletion methyltransferases protein 5, suggesting therapeutic targeting may well tolerated. Here, we will summarize normal vivo functions have been gleaned from mouse studies, expand transcriptional regulated CARM1, finally highlight recent studies identified properties biological settings. This review meant to kindle interest human drug therapies there currently no inhibitors available for use clinical trials.

Language: Английский

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Freedom to err: The expanding cellular functions of translesion DNA polymerases

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(20), P. 3608 - 3621

Published: Aug. 24, 2023

Language: Английский

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An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 17, 2023

Abstract Activation of the KRAS oncogene is a source replication stress, but how this stress generated and it tolerated by cancer cells remain poorly understood. Here we show that induction G12V expression in untransformed triggers H3K27me3 HP1-associated chromatin compaction an RNA transcription dependent manner, resulting fork slowing cell death. Furthermore, elevated ATR necessary sufficient for tolerance -induced to expand stress-tolerant (RSTCs). PrimPol phosphorylated at Ser255, potential Chk1 substrate site, under promotes repriming maintain progression survival ATR/Chk1-dependent manner. However, ssDNA gaps are heterochromatin PrimPol-dependent repriming, leading genomic instability. These results reveal role ATR-PrimPol enabling precancerous survive KRAS-induced clonally with accumulation

Language: Английский

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CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A

Protein & Cell, Journal Year: 2024, Volume and Issue: 15(10), P. 744 - 765

Published: March 13, 2024

Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function CARM1 in triple-negative cancer (TNBC) is still unclear requires further exploration. Here, we report that proliferation, epithelial-mesenchymal transition, stemness TNBC. upregulated multiple cancers its expression correlates with progression. Genome-wide analysis showed recruited by hypoxia-inducible factor-1 subunit (HIF1A) occupy promoters CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, SIX1 critically involved cell cycle, HIF-1 signaling pathway, Wnt VEGF thereby modulating proliferation invasion TNBC cells. We demonstrated physically associated directly interacts HIF1A. Moreover, found ellagic acid, an inhibitor CARM1, can suppress inhibiting CDK4 expression. Our research has determined molecular basis carcinogenesis effective natural inhibitor, which may provide new ideas drugs for therapy.

Language: Английский

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