Publications by authors named "Iljin Kim"

6 Publications

  • Page 1 of 1

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2021 May 4. Epub 2021 May 4.

Obstructive Upper airway Research Laboratory, the Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear.

Objective: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

Methods: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery.

Results: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice.

Conclusions: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.
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http://dx.doi.org/10.1016/j.jaci.2021.04.024DOI Listing
May 2021

Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer.

Oncogene 2020 09 14;39(36):5839-5854. Epub 2020 Aug 14.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

Identification of pro-metastatic genomic alterations is urgently needed to help understand and prevent the fatal course of prostate cancer. Here, we found that the transcription factor EGR3, located at chromosome 8p21.3, is a critical metastasis suppressor. Aberrant deletion of EGR3 was found in up to 59.76% (deep deletions, 16.87%; shallow deletions, 42.89%) of prostate cancer patients. In informatics analysis, EGR3 loss was associated with prostate cancer progression and low survival rates. EGR3 expression inversely correlated with the expressions of epithelial-to-mesenchymal transition (EMT) and metastasis-related gene sets in prostate cancer tissues. In prostate cancer cells, EGR3 blocked the EMT process and suppressed cell migration and invasion. In a mouse model for cancer metastasis, EGR3 overexpression significantly suppressed bone metastases of PC3 and 22Rv1 prostate cancer cells. Mechanistically, EGR3 transcriptionally activated ZFP36, GADD45B, and SOCS3 genes by directly binding to their promoter regions. The EMT-inhibitory and tumor-suppressive roles of the EGR3 downstream genes were identified through in vitro and in silico analyses. Together, our results showed that EGR3 may be a biomarker to predict clinical outcomes and that it plays an important role in the metastatic progression of prostate cancer.
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http://dx.doi.org/10.1038/s41388-020-01418-5DOI Listing
September 2020

Hypoxia-driven epigenetic regulation in cancer progression: A focus on histone methylation and its modifying enzymes.

Cancer Lett 2020 10 6;489:41-49. Epub 2020 Jun 6.

Department of Pharmacology, Cancer Research Institute, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

The mechanism underlying hypoxia-driven chromatin remodeling is a long-lasting question. For the last two decades, this question has been resolved in part. It is now widely agreed that hypoxia dynamically changes the methylation status of histones to control gene expression. Hypoxia-inducible factor (HIF) plays a central role in cellular responses to hypoxia through transcriptional activation of numerous genes. At least in part, the hypoxic regulation of histone methylation is attributed to the HIF-mediated expression of histone modifying enzymes. Protein hydroxylation and histone demethylation have emerged as the oxygen sensing processes because they are catalyzed by a family of 2-oxoglutarate (2OG)-dependent dioxygenases whose activities depend upon the ambient oxygen level. Recently, it has been extensively investigated that the 2OG dioxygenases oxygen-dependently regulate histone methylation. Nowadays, the hypoxic change in the histone methylation status is regarded as an important event to drive malignant behaviors of cancer cells. In this review, we introduced and summarized the cellular processes that govern hypoxia-driven regulation of histone methylation in the context of cancer biology. We also discussed the emerging roles of histone methyltransferases and demethylases in epigenetic response to hypoxia.
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http://dx.doi.org/10.1016/j.canlet.2020.05.025DOI Listing
October 2020

PIN1 transcript variant 2 acts as a long non-coding RNA that controls the HIF-1-driven hypoxic response.

Sci Rep 2019 07 22;9(1):10599. Epub 2019 Jul 22.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

The transcription factor HIF-1 induces the expression of genes that are essential for cell survival and oxygen homeostasis in hypoxic conditions. The prolyl isomerase Pin1 plays a role in the regulation of HIF-1α. However, the mechanism by which Pin1 controls HIF-1α remains controversial. Surprisingly, we here show that a PIN1 transcript downregulates HIF-1α as a long non-coding RNA. Pin1-silencing siRNAs augmented the hypoxia-induced expression of HIF-1α, thereby upregulating the expression of HIF-1 target genes. However, the overexpression of Pin1 protein did not inhibit the hypoxic expression of HIF-1α. Pin1 restoration in Pin1-depleted cells also failed to reverse the induction of HIF-1α by Pin1 knockdown. Unexpectedly, HIF-1α was found to be induced by both siRNAs for PIN1 transcript variants 1/2 and that for PIN1 transcript variants 2/3, indicating that the PIN1 transcript variant 2 (PIN1-v2) is responsible for HIF-1α induction. Mechanistically, PIN1-v2, which is classified as a long non-coding RNA due to early termination of translation, was evaluated to inhibit the transcription of HIF1A gene. In conclusion, PIN1-v2 may function in balancing the HIF-1-driven gene expression under hypoxia.
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http://dx.doi.org/10.1038/s41598-019-47071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646326PMC
July 2019

Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells.

Oncogene 2019 05 18;38(19):3651-3666. Epub 2019 Jan 18.

Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Republic of Korea.

Oxygen is an indispensable element for cell survival and maintenance. Eukaryotic cells are equipped with a series of signaling pathways that cope with hypoxia. The dioxygenase factor inhibiting HIF (FIH) is an oxygen sensor that regulates the transcriptional activity of hypoxia-inducible factor (HIF) through asparaginyl hydroxylation. Given that HACE1 was detected as an FIH-interacting protein in a previous proteomics study, we tested whether the E3 ubiquitin ligase HACE1 is a substrate for FIH. FIH interacted with HACE1, in cells and in vitro, and was determined to hydroxylate HACE1 at the N191 residue within the ankyrin repeat domain. Hydroxylation disrupted the physical association between HACE1 and its representative target, Rac1. Under hypoxic conditions, HACE1 is less hydroxylated due to the inactivation of FIH, and subsequently functions to ubiquitinate the active form of Rac1, leading to the proteasomal degradation of Rac1. Since Rac1 stimulates cell movement, HACE1 inhibits cell migration and invasion in breast cancer by removing active Rac1. Such an effect of HACE1 is reinforced under hypoxia because HACE1 escapes from FIH-mediated hydroxylation. In clinical datasets, HACE1 downregulation is associated with poor outcomes in patients with breast cancer. Taken together, FIH is likely to act as an oxygen sensor that determines oxygen-dependent cancer progression.
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http://dx.doi.org/10.1038/s41388-019-0676-yDOI Listing
May 2019

A novel HIF1AN substrate KANK3 plays a tumor-suppressive role in hepatocellular carcinoma.

Cell Biol Int 2018 Mar 15;42(3):303-312. Epub 2017 Nov 15.

Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

The KN motif and ankyrin repeat domain-containing protein (KANK) family is involved in actin cytoskeleton organization and cell motility. Compared with other KANK members, the biological function of KANK3 is not clear. Here, we identified KANK3 as a new substrate for the oxygen sensor hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), which hydroxylates HIF-1/2α and other ankyrin repeat domain-containing proteins at asparagine residues. An in vitro hydroxylation assay clearly demonstrated asparaginyl hydroxylation of KANK3 by HIF1AN, and mass spectroscopic analysis revealed that KANK3 is hydroxylated at three asparagine residues within the ankyrin repeat domain. Bioinformatics analysis revealed that KANK3 downregulation is correlated with a poor prognosis in several types of cancers, including hepatocellular carcinoma (HCC). In HCC cells, KANK3 knockdown enhanced cell migration and invasion, while its overexpression inhibited these cell behaviors. Interestingly, such effects of KANK3 were not observed under hypoxic conditions, suggesting oxygen-dependent activity of KANK3. Based on these data, we propose that KANK3 acts as a tumor suppressor to control cancer behavior in an oxygen-dependent manner.
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http://dx.doi.org/10.1002/cbin.10895DOI Listing
March 2018