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Stabilization of MOF (KAT8) by USP10 promotes esophageal squamous cell carcinoma proliferation and metastasis through epigenetic activation of ANXA2/Wnt signaling

Li, Peichao; Yang, Lingxiao; Park, Sun Young; Liu, Fanrong; Li, Alex H; Zhu, Yilin; Sui, Huacong; Gao, Fengyuan; Li, Lingbing; Ye, Lan; Zou, Yongxin; Tian, Zhongxian; Zhao, Yunpeng; Costa, Max; Sun, Hong; Zhao, Xiaogang
Dysregulation of MOF (also known as MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not catalytically inactive mutant (MOF-E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and deubiquitinates MOF at lysine 410, which protects it from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription in a JUN-dependent manner, which subsequently activates Wnt/β-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.
PMID: 38317006
ISSN: 1476-5594
CID: 5632852

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells

Li, Alex H; Park, Sun Young; Li, Peiwei; Zhou, Chaoting; Kluz, Thomas; Li, Jingxia; Costa, Max; Sun, Hong
Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.
PMCID:10855786
PMID: 38339062
ISSN: 1422-0067
CID: 5632142

Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer

Li, Ling bing; Yang, Ling xiao; Liu, Lei; Liu, Fan rong; Li, Alex H.; Zhu, Yi lin; Wen, Hao; Xue, Xia; Tian, Zhong xian; Sun, Hong; Li, Pei chao; Zhao, Xiao gang
Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. [Figure not available: see fulltext.]
SCOPUS:85182484923
ISSN: 1671-4083
CID: 5629642

A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes

Ortiz, Angelica; Sun, Hong; Kluz, Thomas; Matsui, Mary S; Carle, Tiffany; Gan, David; Gordon, Terry; Gildea, Lucy; Costa, Max
OBJECTIVE:), is associated with oxidative stress, DNA damage and inflammation, leading to premature signs of skin aging. Because much of the damage results from oxidative stress, we examined the effects of a topical composition containing three antioxidants in an in vitro model system to assess the potential for amelioration of premature aging. The use of multiple antioxidants was of interest based on the typical composition of therapeutic skincare products. It is important to determine the efficacy of multiple antioxidants together and develop a short-term assay for larger scale efficacy testing. METHODS:in the presence and absence of an antioxidant mixture of resveratrol, niacinamide and GHK peptide. Endpoints related to inflammation, premature aging and carcinogenicity were monitored after 5 h of exposure and included IL-6, CXCL10, MMP-1 and NRF2. Differentially expressed genes were monitored by RNA-seq. RESULTS:and suppressed by antioxidants. CONCLUSIONS:Specific signalling pathways known to be correlated with skin inflammation and aging were examined based on their suitability for use in efficacy testing for the prevention of skin damage due to ambient hydrocarbon pollution. Endpoints examined after only 5 h of exposure provide a useful method amenable to high through-put screening. The results obtained reinforce the concept that a multiple antioxidant preparation, topically applied, may reduce pro-inflammatory signalling and cellular damage and thereby reduce premature skin aging due to exposure to rural-derived airborne pollution.
PMID: 37602524
ISSN: 1468-2494
CID: 5598212

Hexavalent chromium inhibits myogenic differentiation and induces myotube atrophy

Park, Sun Young; Liu, Shan; Carbajal, Edgar Perez; Wosczyna, Michael; Costa, Max; Sun, Hong
Hexavalent chromium [Cr(VI)] is extensively used in many industrial processes. Previous studies reported that Cr(VI) exposures during early embryonic development reduced body weight with musculoskeletal malformations in rodents while exposures in adult mice increased serum creatine kinase activity, a marker of muscle damage. However, the impacts of Cr(VI) on muscle differentiation remain largely unknown. Here, we report that acute exposures to Cr(VI) in mouse C2C12 myoblasts inhibit myogenic differentiation in a dose-dependent manner. Exposure to 2 μM of Cr(VI) resulted in delayed myotube formation, as evidenced by a significant decrease in myotube formation and expression of muscle-specific markers, such as muscle creatine kinase (Mck), Myocyte enhancer factor 2 (Mef2), Myomaker (Mymk) and Myomixer (Mymx). Interestingly, exposure to 5 μM of Cr(VI) completely abolished myotube formation in differentiating C2C12 cells. Moreover, the expression of key myogenic regulatory factors (MRFs) including myoblast determination protein 1 (MyoD), myogenin (MyoG), myogenic factor 5 (Myf5), and myogenic factor 6 (Myf6) were significantly altered in Cr(VI)-treated cells. The inhibitory effect of Cr(VI) on myogenic differentiation was further confirmed in freshly isolated mouse satellite cells, a stem cell population essential for adult skeletal muscle regeneration. Furthermore, Cr(VI) exposure to fully differentiated C2C12 myotubes resulted in a decrease in myotube diameter, which was exacerbated upon co-treatment with dexamethasone. Together, our results demonstrate that Cr(VI) inhibits myogenic differentiation and induces myotube atrophy in vitro.
PMCID:10591800
PMID: 37742872
ISSN: 1096-0333
CID: 5605222

CircABCA13 acts as a miR-4429 sponge to facilitate esophageal squamous cell carcinoma development by stabilizing SRXN1

Luo, Junwen; Tian, Zhongxian; Zhou, Yongjia; Xiao, Zhaohua; Park, Sun Young; Sun, Hong; Zhuang, Ting; Wang, Yongjie; Li, Peiwei; Zhao, Xiaogang
Circular RNAs (circRNAs) play a pivotal role in the tumorigenesis and progression of various cancers. However, the role and mechanisms of circABCA13 in esophageal squamous cell carcinoma (ESCC) are largely unknown. Here, we reported that circABCA13, a novel circular RNA generated by back-splicing of the intron of the ABCA13 gene, is highly expressed in ESCC tumor tissues and cell lines. Upregulation of circABCA13 correlated with TNM stage and a poor prognosis in ESCC patients. While knockdown of circABCA13 in ESCC cells significantly reduced cell proliferation, migration, invasion, and anchorage-independent growth, overexpression of circABCA13 facilitated tumor growth both in vitro and in vivo. In addition, circABCA13 directly binds to miR-4429 and sequesters miR-4429 from its endogenous target, SRXN1 mRNA, which subsequently upregulates SRXN1 and promotes ESCC progression. Consistently, overexpression of miR-4429 or knockdown of SRXN1 abolished malignant behavior promotion of ESCC results from circABCA13 overexpression in vitro and in vivo. Collectively, our study uncovered the oncogenic role of circABCA13 and its mechanism in ESCC, suggesting that circABCA13 could be a potential therapeutic target and a predictive biomarker for ESCC patients.
PMCID:10323080
PMID: 37017121
ISSN: 1349-7006
CID: 5536412

Effects of energy drinks on myogenic differentiation of murine C2C12 myoblasts

Park, Sun Young; Karantenislis, Georgia; Rosen, Hannah T; Sun, Hong
Energy drinks, often advertised as dietary supplements that enhance physical and mental performance, have gained increasing popularity among adolescents and athletes. Several studies on individual ingredients such as caffeine or taurine have reported either adverse or favorable influences on myogenic differentiation, a key process in muscle regeneration to repair microtears after an intense workout session. However, the impact of different energy drinks with various formulas on muscle differentiation has never been reported. This study aims to examine the in vitro effects of various energy drink brands on myogenic differentiation. Murine C2C12 myoblast cells were induced to differentiate into myotubes in the presence of one of eight energy drinks at varying dilutions. A dose-dependent inhibition of myotube formation was observed for all energy drinks, supported by reduced percentage of MHC-positive nuclei and fusion index. Moreover, expression of myogenic regulatory factor MyoG and differentiation marker MCK were also decreased. Furthermore, given the variation in formulas of different energy drinks, there were remarkable differences in the differentiation and fusion of myotubes between energy drinks. This is the first study to investigate the impact of various energy drinks on myogenic differentiation and our results suggest an inhibitory effect of energy drinks in muscle regeneration.
PMCID:10213057
PMID: 37231025
ISSN: 2045-2322
CID: 5541792

Experiences and needs of older adults at different stages of cerebral infarction based on trajectory theory-A qualitative study

Tang, Xianping; Sun, Hong; Ge, Song; Han, Shuyu; Li, Ying; Wu, Bei
BACKGROUND:In recent years, stroke has become the second leading cause of death worldwide, and the incidence and mortality of ischemic stroke have increased significantly. This study mainly aimed to explore the experiences and needs of older adults at different stages of cerebral infarction based on the chronic illness trajectory theory. METHODS:Data were collected from 22 older adults experiencing the onset, acute, and stable stages of stroke through semi-structured interviews and were analyzed using Colaizzi's descriptive phenomenological approach. RESULTS:Multiple themes and subthemes emerged on the experiences and needs of older adults at different stages of cerebral infarction based on the three dimensions of the long-term disease trajectory theory: illness-related work, biographical work, and everyday life work. Seven themes were extracted for illness-related work, six for biographical work, and eight for everyday life work. DISCUSSIONS/CONCLUSIONS:The treatment, nursing, and rehabilitation of cerebral infarction are complex. This study indicated that patients after cerebral infarction have different experiences and needs for illness-related work. They also have distinctive and dynamically changing demands for biographical work and everyday life work. CONCLUSIONS:The experiences and needs of older patients with cerebral infarction changed dynamically at different stages of the disease. Healthcare professionals should develop effective interventions targeting these needs at various disease stages, provide patients with continuous support to shape their disease trajectories, and maintain patients' stability.
PMID: 36322506
ISSN: 2054-1058
CID: 5387492

Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Gorr, Matthew W; Wold, Loren E; Cohen, Mitchell D
First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.
PMID: 35055737
ISSN: 1660-4601
CID: 5131772

Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment

Murphy, Anthony J; Li, Alex H; Li, Peichao; Sun, Hong
The ability for cells to harness alternative splicing enables them to diversify their proteome in order to carry out complex biological functions and adapt to external and internal stimuli. The spliceosome is the multiprotein-RNA complex charged with the intricate task of alternative splicing. Aberrant splicing can arise from abnormal spliceosomes or splicing factors and drive cancer development and progression. This review will provide an overview of the alternative splicing process and aberrant splicing in cancer, with a focus on serine/arginine-rich (SR) proteins and their recently reported roles in cancer development and progression and beyond. Recent mapping of the spliceosome, its associated splicing factors, and their relationship to cancer have opened the door to novel therapeutic approaches that capitalize on the widespread influence of alternative splicing. We conclude by discussing small molecule inhibitors of the spliceosome that have been identified in an evolving era of cancer treatment.
PMCID:9027816
PMID: 35463320
ISSN: 2234-943x
CID: 5217242