Menin regulates YBX1 nuclear translocation to drive HKDC1 transcription and restrain glycolysis in pancreatic ductal adenocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE301126 | GEO | 2025/09/03
REPOSITORIES: GEO
Similar Datasets
Project description:Menin regulates YBX1 nuclear translocation to drive HKDC1 transcription and restrain glycolysis in pancreatic ductal adenocarcinoma
| PRJNA1284095 | ENA
Project description:In order to identify YBX1 binding sites on endogenous RNA, we performed HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Licatalosi D, et al. 2008, Nature 456:464-U22)
2015-05-08 | E-GEOD-63604 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using a combination of in vitro and in vivo tools, we examined the role of HKDC1 in HCC development and progression. Importantly, HKDC1 ablation stops HCC development and progression via action by promoting metabolic reprogramming and a shift of glucose flux away from the TCA cycle. HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy which cannot be compensated by enhanced glucose uptake. Moreover, we show that the interaction of HKDC1 with the mitochondria is essential for its role in HCC progression, and without this mitochondrial interaction mitochondrial dysfunction occurs. HKDC1 is highly expressed in HCC cells, but only to a minimal degree in hepatocytes under normal conditions therefore targeting HKDC1, specifically its interaction with the mitochondria, reveals a highly selective approach to target cancer cells in HCC.
2021-11-21 | GSE188774 | GEO
Project description:In order to identify YBX1 binding sites on tRNA fragments, we performed small-RNA HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Chi SW, et al. 2009, Nature 460:479)
2015-05-08 | E-GEOD-63597 | biostudies-arrayexpress
Project description:YBX1 is a multifunctional protein involved in the control of transcription and translation. We identified YBX1 as an target of MEK/ERK signaling in colorectal cancer cell lines. We performed a ChIP-chip analysis of HCT116 cells to identify new potential target genes of YBX1. Comparison of input DNA fragments with fragments coprecipitated with YBX1 in HCT116 cells.
2010-10-09 | E-GEOD-18337 | biostudies-arrayexpress
Project description:In order to identify YBX1-dependent targets that are modulated under hypoxic conditions, we used control and YBX1 knockdown cells grown under normoxia and hypoxia to profile gene expression levels. Control and YBX1-knockdown cells were grown and profiled under hypoxia and normoxia to identify YBX1-dependent hypoxia-induced target transcripts.
2015-05-08 | E-GEOD-63562 | biostudies-arrayexpress
Project description:Metabolic-associated steatohepatitis (MASH), the inflammatory stage of MASLD, will soon be one of the primary causes of liver-related complications, including advanced fibrosis and hepatocellular carcinoma. Its steady increase in both the US and the global population is devastating. Between the two genders, more women are suffering from MASH compared to the man due to estrogen deficiency caused by polycystic ovary syndrome or menopause. Our published data shows a clear positive association between the progression of liver disease and the expression of novel hexokinase HKDC1 in the liver. Targeting HKDC1, which is highly expressed in pathological hepatocytes (in MASH) but negligible in normal hepatocytes, represents a highly selective approach. Therefore, we hypothesized that liver-specific deletion of HKDC1 will protect against diet-induced obesity and the progression of MASH to fibrosis. We used an early-onset liver knockout (LKO) of HKDC1 by crossing HKDC1 floxed mice with Albumin Cre mice to test our hypothesis. We fed the Western Diet to HKDC1LKO female mice along with HKDC1 floxed mice (HKDC1fl/fl; as Controls) for 28 weeks. Our data shows that HKDC1 deletion significantly decreases body weight and fat mass compared to HKDC1fl/fl mice with no changes in food intake and energy expenditure. Knockout mice have better glucose tolerance and lower fasting glucose levels than HKDC1fl/fl mice. Our data also shows that the knockout group has smaller livers, healthier liver parameters, less steatosis, and lower NAS and fibrosis scores. Furthermore, HKDC1 knockout alters hepatic gene expression, and we found significantly low proinflammatory and profibrogenic gene expression in the LKO mice. Although we did not see any changes in triglyceride levels, there was a significant reduction of serum cholesterol concomitant with enhanced expression of cholesterol metabolism genes in the knockout group. Our data suggest a promising protective role of HKDC1 deletion against diet-induced obesity and MASH mice.
2024-11-27 | GSE283058 | GEO
Project description:Hexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. We found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models. Molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells. Overall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.
2024-10-02 | GSE278074 | GEO
Project description:Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent H3K4me3 modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1’s protein kinase activity, but not its hexokinase activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression.
2025-01-07 | PXD059464 | Pride
Project description:To investigate the tumorigenic function of HKDC1 in vivo, we established A549 cell lines in which HKDC1 has been knockout by CRISPER/Cas9 genome editing. We then performed gene expression profiling analysis using data obtained from RNA-seq of 6 different tumors from sgCtrl or sgHKDC1-1 groups.
2024-12-18 | GSE216107 | GEO