Ask about this productRelated genes to: ACSS2 Blocking Peptide
- Gene:
- ACSS2 NIH gene
- Name:
- acyl-CoA synthetase short chain family member 2
- Previous symbol:
- ACAS2
- Synonyms:
- ACS, ACSA, AceCS, dJ1161H23.1
- Chromosome:
- 20q11.22
- Locus Type:
- gene with protein product
- Date approved:
- 2001-09-17
- Date modifiied:
- 2017-06-13
Related products to: ACSS2 Blocking Peptide
Related articles to: ACSS2 Blocking Peptide
- Central metabolites function as essential co-substrates for chromatin-modifying enzymes, directly linking cellular metabolism to chromatin regulation. Accordingly, whole-cell fluctuations in co-substrate availabilities have been shown to promote diverse phenotypes through chromatin-dependent mechanisms. There is emerging evidence that metabolic enzymes producing co-substrates for chromatin modifying enzymes can exist in the nucleus, suggesting that nucleus-specific metabolite availability regulates chromatin state. Here, we developed CRISPRm (CRISPR metabolite) to assess how nucleus-specific metabolic perturbations influence chromatin function. Five dCas9-metabolic enzyme fusions ( ., dCas9-ACSS2, -NMNAT1, -MAT2A, -GDH, and -AHCY) were used to modulate nuclear levels of essential co-substrates involved in histone (de)acetylation and (de)methylation reactions. Transient expression of all dCas9 fusions in HEK293T cells induced distinct global changes in gene expression patterns, with dCas9-ACSS2 (acetyl-CoA producing) and NMNAT1 (NAD producing) eliciting large opposing changes in gene expression, suggesting transcriptional responses to nuclear acetyl-CoA and NAD production may be directly facilitated by acetylation or deacetylation reactions, respectively. Targeting dCas9-ACSS2 and -NMNAT1 to promoters of select candidate genes revealed enhanced transcriptional modulation. dCas9-ACSS2 upregulated, and dCas9-NMNAT1 downregulated genes showed basal enrichment of H3K9ac, H3K18ac, H3K27ac, H3K4me3, and p300, suggesting these genomic loci reside within epigenetic environments susceptible to fluctuations in acetyl-CoA and NAD availability. Of significant genes altered, dCas9-MAT2A (SAM producing) increased expression of 72% whereas dCAS9-GDH (alpha-ketoglutarate producing) decreased expression of 79%. Surprisingly, dCAS9-AHCY (SAH hydrolysis) led to down-regulation of shared genes up-regulated by dCas9-MAT2A. The observations amongst the methylation-specific enzymes revealed unexpected and unique gene-regulatory sensitivities to SAM, SAH and alpha-ketoglutarate. Together, these results demonstrate the utility of CRISPRm in studying nuclear metabolic regulation of transcription and provide strong evidence that perturbations in nuclear co-substrates do not lead to a large mass- action changes in chromatin acetylation/methylation but rather to modulation of select chromatin-modifying enzymes with targeted transcription responses. - Source: PubMed
Publication date: 2026/05/10
Biesbrock Kellen VHaws Spencer ACormaty HarshiniSridharan RupaDenu John M - EZH2 inhibitors show limited efficacy in solid versus hematologic cancers, but the underlying mechanisms are unknown. We investigated whether tumor-type-specific adaptive responses underlie this differential sensitivity. - Source: PubMed
Publication date: 2026/05/16
Lin XiaoyunSong YuePeng QingqinTu SanfangYang PeidongZhou LiyanLi Yuhua - Lenvatinib, a first-line tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC), faces clinical challenges due to acquired drug resistance. While metabolic reprogramming has been implicated in therapeutic resistance, the precise mechanistic links remain elusive. Here, we identified ACSS2-mediated metabolic-epigenetic crosstalk as a critical driver of Lenvatinib resistance. Transcriptomic and metabolomic profiling identified enhanced pyruvate metabolism in resistant HCC cells, with ACSS2 expression showing the strongest association with Lenvatinib resistance. Genetic manipulation experiments demonstrated that ACSS2 dictates therapeutic sensitivity, with knockdown restoring drug response and overexpression conferring resistance. Mechanistically, ACSS2-driven palmitate biosynthesis facilitates EGFR palmitoylation, which shields the receptor from ubiquitin-dependent degradation. This stabilization sustains oncogenic EGFR signaling, ultimately mediating therapeutic escape. Crucially, pharmacological inhibition of ACSS2 synergized with Lenvatinib to overcome resistance in both subcutaneous and hydrodynamic transfection HCC models. Our findings not only delineate the ACSS2/EGFR axis as a metabolic vulnerability in resistant HCC but also propose ACSS2-targeted therapy as a promising strategy to reverse Lenvatinib resistance, providing a novel therapeutic approach for advanced HCC management. - Source: PubMed
Publication date: 2026/05/14
Xu HaoWang HaoYu Shi-ZheZou Tian-TianXie Sun-ZheShen Ke-YuZhang ChenXu Jian-FengPan Jun-JieYang SamIXu DaChen Ji-SongZhao JingXie FangSu Ying-HanZhu Wen-WeiQin Lun-Xiu - Sepsis-induced myocardial injury (SIMI) is a severe complication of sepsis with limited mechanism-based therapies. We investigated whether Relaxin-3 attenuates SIMI and modulates macrophage inflammatory responses. - Source: PubMed
Publication date: 2026/05/05
Yang YuxinLiu XiaoqiXue JiaxinYun ChengchengDou YingWang JingzhiZhang Xiaohui - Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybutyrate (BHB), the main component of ketone bodies, not only serves as an ancillary fuel substituting for glucose but also induces anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone β-hydroxybutyrylation (Kbhb). Recent research has found that BHB has a positive therapeutic effect on OP, but the underlying molecular mechanism remains unclear. In this study, we established OP animal models induced by estrogen deficiency and type 2 diabetes using ovariectomized (OVX) and db/db mice, respectively, and administered BHB to OP mice via free drinking in vivo. Our results indicated that BHB increased bone mineral density (BMD), improved bone microstructure, and inhibited OC formation. Additionally, BHB upregulated the levels of PanKbhb, H3K9bhb, and H3K27bhb modifications in the bone tissue of OP mice. In vitro, we found that BHB or β-hydroxybutyryl-CoA (BHB-CoA) could inhibit RANKL-induced OC differentiation and bone resorption, and upregulate histone Kbhb levels in a concentration-dependent manner. Furthermore, the effects of BHB or BHB-CoA-induced histone Kbhb were reversed by inhibiting the activity of acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300. In summary, our data reveal that BHB may alleviate bone loss caused by estrogen deficiency and type 2 diabetes through ACSS2/P300-induced histone Kbhb. - Source: PubMed
Publication date: 2026/04/30
He YanqiuMou ChenglongTang MinLuo LiZhou TingtingCheng XiLi DongzeLuo ChangfangGuo ManHu JinboLi QifuWan QinDeng LiyunLi YueZhang HaiqiangNi QiongyuXu YongGao ChenlinHuang Wei