Tumorigenic effect of knockout HKDC1 on A549 in vivo
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216107 | GEO | 2024/12/18
REPOSITORIES: GEO
Similar Datasets
Project description:Tumorigenic effect of knockout HKDC1 on A549 in vivo
| PRJNA892099 | ENA
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: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:Histone methyltransferases KMT2A (also known as mixed lineage leukemia 1, MLL1) can convert H3K4me1 to H3K4me2 with limited activity. However, it fully trimethylates H3K4 when associated with core subunits, including WDR5, RBBP5, ASH2L, and DPY30. We demonstrated that HKDC1 binds and phosphorylates RBBP5, promoting the assembly of MLL1 complex and the activating H3K4me3. Consequently, HKDC1 transcriptionally activates gene expression. We used CUT&Tag to study H3K4me3 levels of the promoter regions regulated by HKDC1 and RBBP5. Here, we also performed RNA-seq assay in PLC cells with HKDC1 or RBBP5 knocked down to study the role of HKDC1 and RBBP5 in regulating gene expression.
2025-01-12 | GSE275644 | 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:Histone methyltransferases KMT2A (also known as mixed lineage leukemia 1, MLL1) can convert H3K4me1 to H3K4me2 with limited activity. However, it fully trimethylates H3K4 when associated with core subunits, including WDR5, RBBP5, ASH2L, and DPY30. We demonstrated that HKDC1 binds and phosphorylates RBBP5, promoting the assembly of MLL1 complex and the activating H3K4me3. Here, we used CUT&Tag to study H3K4me3 levels of the promoter regions regulated by HKDC1 and RBBP5. We knocked down HKDC1 or RBBP5 in PLC cells and performed CUT&Tag assay.
2025-01-12 | GSE275531 | GEO
Project description:A549 cells were co-transfected with CRISPR/Cas9 (containing sgRNA and GFP) and HDR donor plasmids (containing RFP and puromycin). The genetic editing cells were selected by puromycin. And then, we performed RNA sequencing for transcription profiling of A549 RB1 RB1 wild-type/knockout cell lines. The raw data were processed with Tophat and cuffdiff for gene expression analysis.
2020-08-25 | GSE132722 | GEO
Project description:Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation sequencing (ChIP)-quantitative PCR (qPCR), we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB–HKDC1 axis was essential for PINK1/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels (VDACs), with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and mitochondria-lysosome contact.Interestingly, the kinase regulated mitophagy and lysosomal repair independently from its function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage–induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a novel factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.
2024-01-31 | GSE226743 | GEO
Project description:A primary role of the liver is to regulate whole body glucose homeostasis. Glucokinase (GCK) is the main hexokinase (HK) expressed in hepatocytes and functions to phosphorylate the glucose that enters via GLUT transporters to become glucose-6-phosphate (G6P), which subsequently commits glucose to enter downstream anabolic and catabolic pathways. In the recent years, Hexokinase Domain-Containing-1 (HKDC1), a novel 5th HK, has been characterized by our group and others. Its expression profile varies but has been identified to have low basal expression in normal liver but increases during states of stress including pregnancy, nonalcoholic fatty liver disease (NAFLD), and liver cancer. Here, we have developed a stable overexpression model of hepatic HKDC1 in mice to examine its effect on metabolic regulation. We found that HKDC1 overexpression, over time, causes impaired glucose homeostasis in male mice and shifts glucose metabolism towards anabolic pathways with an increase in nucleotide synthesis. Furthermore, we observed these mice to have larger liver sizes due to greater hepatocyte proliferative potential and cell size, which in part, is mediated via Yes-associated protein (YAP) signaling
2023-03-20 | GSE227535 | GEO