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JMJD2B-Induced Amino Acid Alterations Enhance the Survival Of Theranostics 2020, Vol. 10, Issue 13 5763 Ivyspring International Publisher Theranostics 2020; 10(13): 5763-5777. doi: 10.7150/thno.38087 Research Paper JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy Juan Tan1*, Hao-Lian Wang1*, Jie Yang2, Qian-Qian Liu1, Chun-Min Li1, Yun-Qian Wang1, Lin-Na Fu1, Qin-Yan Gao1, Ying-Xuan Chen1 and Jing-Yuan Fang1 1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease;145 Middle Shandong Road, Shanghai 200001, China. 2. Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Education Ministry for Cell Differentiation and Apoptosis, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine. 280 South Chongqing Rd, Shanghai 200025, China. * These authors contributed equally to this work. Corresponding author: Ying-Xuan Chen; Add: 145 Middle Shandong Rd, Shanghai 200001, China; Fax/Tel: (+86)-21-63266027; Email: [email protected] © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.07.02; Accepted: 2020.04.13; Published: 2020.04.27 Abstract Rationale: Post-translational modifications have emerged as vital players in alterations to tumor metabolism, including amino acid metabolic reprogramming. Jumonji domain-containing protein 2B (JMJD2B) enhances colorectal cancer (CRC) cell survival upon glucose deficiency. In the present study, we hypothesized that JMJD2B affects tumor cell amino acid metabolism in CRC and consequently promotes survival of CRC cells upon glucose deprivation. Methods: Non-target metabolic profiling was used to evaluate the roles of JMJD2B in CRC cell metabolism under glucose starvation. The roles of amino acid alterations induced by JMJD2B on CRC cell survival were determined by cell viability, immunoblotting, and clonogenic assays, and flow cytometry. The underlying mechanisms by which JMJD2B affected CRC cell metabolism were assessed using immunofluorescence staining, chromatin immunoprecipitation assays, electron microscopy in CRC cell lines, and using xenograft models. The correlation between JMJD2B and LC3B expression in human CRC specimens was assessed using immunohistochemistry. Results: Profound metabolic reprogramming was detected in JMJD2B knockdown CRC cells under glucose deficiency, especially those involving amino acid metabolites. Silencing of JMJD2B reduced the levels of certain amino acids that were induced by glucose deficiency. Among these amino acids, asparagine (Asn), phenylalanine (Phe), and histidine (His) promoted CRC cell survival under glucose starvation when JMJD2B was knocked down. Mechanistically, downregulation of JMJD2B inhibited autophagy in CRC cells through epigenetic regulation of microtubule associated protein 1 light chain 3 beta (LC3B), and subsequently decreased intracellular amino acid (Asn, Phe, His) levels under glucose deprivation, thus suppressing the survival of CRC cells. Using a nude mouse xenograft model, we verified that inhibiting JMJD2B could decrease the levels of amino acids (Asn, Phe, His). In addition, the inhibitory effects of JMJD2B-knockdown on tumor growth and amino acids level were rescued by overexpression of LC3B. Furthermore, we observed that the high expression of LC3B was more likely detected in tissuses with high expression of JMJD2B (P < 0.001) in 60 human CRC tissues. Conclusion: These results indicated that JMJD2B sustained the intracellular amino acids derived from autophagy in CRC cells upon glucose deficiency, partly through epigenetic regulation of LC3B, thus driving the malignancy of CRC. Key words: JMJD2B, CRC, amino acids metabolism, autophagy, LC3B http://www.thno.org Theranostics 2020, Vol. 10, Issue 13 5764 In the present study, we detected marked Introduction metabolic reprogramming after JMJD2B knockdown Colorectal cancer (CRC) is a frequently under glucose deficiency conditions in CRC cells, diagnosed malignancy and is the second leading with amino acid metabolites being the most affected cause of cancer death, resulting in a significant by lack of JMJD2B. Metabolomic analysis showed that economic burden, especially in the developing world 27 amino acid-related metabolites were upregulated [1]. Therefore, it is important to better understand the under glucose deprivation, of which 15 were molecular mechanisms that contribute to the downregulated by JMJD2B knockdown, including aggressiveness of CRC. Although previous studies five amino acids. Among these five amino acids, have identified multiple cellular processes that asparagine (Asn), phenylalanine (Phe), and histidine promote CRC tumorigenesis, including genomic and (His) promoted CRC cell survival under glucose epigenomic changes, the precise mechanism remains deprivation in a background of JMJD2B knockdown. unknown. Mechanistically, JMJD2B promoted autophagy during Jumonji domain-containing protein 2B (JMJD2B), glucose deprivation to sustain intracellular amino also known as KDM4B (lysine demethylase 4B), acid levels (Asn, Phe, His) in CRC cells, via epigenetic mainly removes tridimethylation (me3/2) at the nine regulation of microtubule associated protein 1 light lysine (K) residues of histone H3 [2]. Our previous chain 3 beta (LC3B). Collectively, our findings study showed that JMJD2B is highly expressed in describe a new regulatory mechanism of glucose CRC cancer tissues [3], and is overexpressed in a deprivation-mediated CRC metabolism, identifying variety of tumors [2]. Silencing of JMJD2B caused cell JMJD2B as a promising target for CRC therapy. cycle arrest, apoptosis, and senescence of CRC cells, thus inhibiting their survival [3, 4]. The abnormal Methods growth of functional blood vessels associated with rapid cancer cell proliferation in solid tumors results Cell lines, plasmids, adenovirus, and lentivirus in some regions within the tumors being temporarily Human CRC cell lines HCT116 and SW480 were or continuously under stress in an unfavorable purchased from the ATCC (the American Type microenvironment, particularly nutritional deficiency Culture Collection, Manassas, VA, USA). All cell lines or hypoxia [5-7]. The expression of JMJD2B was were grown in a humidified 5% CO2-containing upregulated under glucose deficiency or hypoxia, and atmosphere incubator at 37 °C. For glucose deficiency, JMJD2B could promote the survival of CRC cells 48 h after seeding, the cells were washed briefly using under these conditions [4, 8]. However, it is unclear phosphate-buffered saline (PBS) and cultured in how JMJD2B promotes the survival of CRC cells glucose-free Roswell Park Memorial Institute (RPMI) under stress in the unfavorable tumor 1640 medium (Gibco BRL, Gaithersburg, MD, USA) microenvironment. for the indicated times. RPMI 1640 media without Tumor cells can adapt to changes in their amino acids and glucose was purchased from US unfavorable microenvironment by increasing the Biological (catalog no. #R9010-01, Swampscott, MA, utilization of amino acids. Amino acids are used as USA). The amino acids were added into the amino intermediate metabolites to synthesize important acids-free and glucose-free medium for the indicated biological molecules, e.g., nucleotides, lipids, times as follows: Asn (2 mM, catalog no. #A4159), Phe glutathione, and carbon units; they can also be (2 mM, catalog no. #P5482), His (2 mM, catalog no. oxidized in the tricarboxylic acid cycle (TCA) instead #H5659), and hydroxy-proline (Hyp, 2 mM, catalog of glucose to produce more ATP and NADH; some no. #H5534) [12]; all of which were purchased from could promote accumulating reductive glutathione Merck (St. Louis, MO, USA). The siRNA-resistant (GSH) and reduce reactive oxygen species [9, 10]. For JMJD2B wild-type plasmid (pCMV-HA-JMJD2B-WT), instance, the serine biosynthesis pathway was the H189A/E191Q mutant plasmid (pCMV-HA- activated under glucose deprivation conditions [11]. JMJD2B-MT), and the pCMV-GFP-LC3B plasmid Our previous study found that JMJD2B regulated were purchased from GENEray Biotech (Shanghai, many cellular processes and signaling pathways China). Short hairpin RNA (shRNA) adenovirus under hypoxia, in which cellular metabolic processes constructs targeting JMJD2B were purchased from and metabolic pathways were the most significant OBiO Technology (Shanghai, China). The lentivirus part, including amino acid metabolism [3]. Therefore, targeting the LC3B gene was purchased from we hypothesized that JMJD2B might affect tumor cell Genechem (Shanghai, China), which was used to amino acid metabolism in CRC and consequently establish HCT116 cells stably overexpressing LC3B. promote cellular survival in CRC cells upon glucose deprivation. http://www.thno.org Theranostics 2020, Vol. 10, Issue 13 5765 RNA interference (glutamine-hydrolyzing) (ASNS) (catalog no. Small interfering RNAs (siRNAs) specifically #14681-1-AP, 1:2000, Proteintech, Chicago, IL, USA); targeting JMJD2B (GenePharma, Shanghai, China) anti-histidine ammonia-lyase (HAL) (catalog no. # comprised the following sequences: JMJD2B: H00003034-M04, 1:2000, Abnova, Taipei, Taiwan); siRNA-1, 5′-GCGCAGAAUCUACCAACUU-3′, anti-α-tubulin (catalog no. #ab18251, 1:2000,
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