Demethylation of the HACE1 gene promoter inhibits the proliferation of human liver cancer cells

Yu, Zhijun; Li, Yinyin; Han, Tao; Liu, Zhaozhe

doi:10.3892/ol.2019.10139

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…In the present study, propofol >120 µmol/l exhibited little inhibition; however, the specific underlying mechanism requires further investigation, although it was hypothesized that the concentration of propofol reached saturation at 120 µmol/l. HACE1 is frequently downregulated or lost in numerous types of tumor, such as lung and liver cancer, and acts as a tumor suppressor by ubiquitinating OPTN and activating selective autophagy (18,24). The study found that propofol promoted HACE1 expression levels by demethylating HACE1 gene promoter, which activated HACE1-OPTN axis-mediated autophagy.…”

Section: Discussionmentioning

confidence: 87%

“…HACE1 is frequently downregulated or lost in numerous types of tumor, such as lung and liver cancer, and acts as a tumor suppressor by ubiquitinating OPTN and activating selective autophagy ( 18 , 24 ). The study found that propofol promoted HACE1 expression levels by demethylating HACE1 gene promoter, which activated HACE1-OPTN axis-mediated autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA (gDNA) was extracted from A549 cells treated in the presence or absence of propofol using the standard phenol-chloroform extraction method (23). Then, gDNA was treated with bisulfite using the CpGenome Turbo Bisulfite Modification kit (EMD Millipore) according to the manufacturer's instructions (24). The modified DNA was amplified using Platinum Taq DNA Polymerase (Thermo Fisher Scientific, Inc.) with the respective primer sets (Table II) that recognize bisulfite-modified DNA only.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

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Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells

Yang

Zhao

et al. 2020

Oncol Lett

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Propofol (2,6-diisopropylphenol) is one of the most commonly used intravenous anesthetics and possesses a number of non-anesthetic effects, including antitumor function. The aim of the present study was to elucidate the antitumor molecular mechanism of propofol on A549 and H1299 cells. A549 and H1299 cells were treated in the presence or absence of different concentrations (0, 60 or 120 µmol) of propofol for different durations (0, 24, 48 or 72 h), and proliferation was detected by MTT and colony formation assays; the protein levels of optineurin (OPTN) ubiquitination, HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), methyl-CpG binding domain protein 3 (MBD3) and Microtubule-associated protein 1A/1B-light chain 3 were detected by immunoblotting or quantitative (q)PCR; the methylation state of the HACE1 gene promoter was detected by bisulfite DNA sequencing; and binding of MBD3 on HACE1 gene promoter was detected by chromatin immunoprecipitation-qPCR. Propofol inhibited proliferation of A549 and H1299 cells and promoted HACE1-OPTN axis-mediated selective autophagy activity by increasing the protein expression levels of HACE1 via demethylating its promoter region. Furthermore, propofol promoted expression levels of MBD3 and binding to the-1,000 to-1 bp (transcription start site) region of HACE1 gene promoter. MBD3-knockdown experiments indicated that propofol inhibited proliferation of A549 cells in a MBD3-dependent manner. Thus, the findings of the present study provided a potential antitumor molecular mechanism mediated by propofol.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Cell Proliferation Assaymentioning

confidence: 99%

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Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells

Yang

Zhao

et al. 2020

Oncol Lett

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“…First identified in 2004, HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1; 909 residues) has been shown to take part in various cellular processes. For example, HACE1 is best known as a tumor suppressor as altered HACE1 expression levels have been observed in various cancers including colorectal, breast, liver, kidney, osteosarcoma, lymphoma and gastric cancer [50][51][52][53][54]. HACE1 contains six ankyrin repeats near its N-terminus that likely take part in HACE1-substrate recognition and protein-protein interactions (Figure 2).…”

Section: Hace1 a Prominent Tumor Suppressor With Dual Functionmentioning

confidence: 99%

“…Low expression levels of HACE1 have also been observed in other cancer cell lines. For instance, it was found that the methylation of the HACE1 promoter resulted in decreased HACE1 expression in liver cancer cells, which in turn decreased HACE1's ability to ubiquitylate its identified substrates optineurin (OPTN) and microtubule-associated proteins 1A/1B light chain 3B protein [53]. Many different substrates of HACE1 have been identified to date (summarized in [4]), including β2-adrenergic receptor (ß2AR) [58], OPTN [59], retinoic acid receptor beta (RAR-β) [57], tumor necrosis factor receptor-2 (TNFR2) [60], and various Ras-related [55]), which is likely involved in HACE1 substrate binding and recognition, and a HECT domain (HECTN-lobe in green, HECTC-lobe in blue; PDB 6JX5 [35]) found at HACE1's C-terminus that is required of ubiquitylation activity.…”

Section: Hace1 a Prominent Tumor Suppressor With Dual Functionmentioning

confidence: 99%

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

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HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner

et al. 2021

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Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1–/– mice in murine KRasG12D-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.

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Demethylation of the HACE1 gene promoter inhibits the proliferation of human liver cancer cells

Cited by 11 publications

References 26 publications

Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells

Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner

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Demethylation of the HACE1 gene promoter inhibits the proliferation of human liver cancer cells

Cited by 11 publications

References 26 publications

Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549&nbsp;cells

Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549&nbsp;cells

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner

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Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells

Demethylation of <em>HACE1</em> gene promoter by propofol promotes autophagy of human A549 cells