Browsing by Author "Jin, Hong Ri"

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    Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK
    (Springer Nature, 2019-04-05) Jin, Hong Ri; Du, Charles H.; Wang, Chong-Zhi; Yuan, Chun-Su; Du, Wei; Pathology and Laboratory Medicine, School of Medicine
    Ginseng is one of the most commonly used herbs that is believed to have a variety of biological activities, including reducing blood sugar and cholesterol levels, anti-cancer, and anti-diabetes activities. However, little is known about the molecular mechanisms involved. In this study, we showed that protopanaxadiol (PPD), a metabolite of the protopanaxadiol group ginsenosides that are the major pharmacological constituents of ginsengs, significantly altered the expression of genes involved in metabolism, elevated Sestrin2 (Sesn2) expression, activated AMPK, and induced autophagy. Using CRISPR/CAS9-mediated gene editing and shRNA-mediated gene silencing, we demonstrated that Sesn2 is required for PPD-induced AMPK activation and autophagy. Interestingly, we showed that PPD-induced Sesn2 expression is mediated redundantly by the GCN2/ATF4 amino acid-sensing pathway and the PERK/ATF4 endoplasmic reticulum (ER) stress pathway. Our results suggest that ginseng metabolite PPD modulates the metabolism of amino acids and lipids, leading to the activation of the stress-sensing kinases GCN2 and PERK to induce Sesn2 expression, which promotes AMPK activation, autophagy, and metabolic health.
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    Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death
    (Wiley, 2019-03) Jin, Hong Ri; Du, Charles H.; Wang, Chong-Zhi; Yuan, Chun-Su; Du, Wei; Pathology and Laboratory Medicine, School of Medicine
    Protopanaxadiol (PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent 5-FU. However, the mechanism by which PPD promotes cancer cell death is not clear. In this manuscript, we showed that PPD activated p53 and ER stress and induced expression of BH3-only proteins Puma and Noxa to promote cell death. Induction of Puma by PPD was p53-dependent while induction of Noxa was p53-independent. On the other hand, PPD also induced pro-survival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced PPD-induced cell death. Interestingly, PPD inhibited expression of genes involved in fatty acid and cholesterol biosynthesis and induced synergistic cancer cell death with fatty acid synthase inhibitor cerulenin. As PPD-induced ER stress was not significantly affected by inhibition of new protein synthesis, we suggest PPD may induce ER stress directly through causing lipid disequilibrium.
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    SUMO1 degrader induces ER stress and ROS accumulation through deSUMOylation of TCF4 and inhibition of its transcription of StarD7 in colon cancer
    (Wiley, 2023) Zhao, Yin Quan; Jin, Hong Ri; Kim, Daeho; Jung, Sung Han; Liu, Sheng; Wan, Jun; Lo, Ho-Yin; Fu, Xue Qi; Wang, Quan; Hao, Chunhai; Bellail, Anita C.; Pathology and Laboratory Medicine, School of Medicine
    Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screens has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader’s anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).
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    Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors
    (AAAS, 2021) Bellail, Anita C.; Jin, Hong Ri; Lo, Ho-Yin; Jung, Sung Han; Hamdouchi, Chafiq; Kim, Daeho; Higgins, Ryan K.; Blanck, Maximilian; le Sage, Carlos; Cross, Benedict C. S.; Li, Jing; Mosley, Amber L.; Wijeratne, Aruna B.; Jiang, Wen; Ghosh, Manali; Zhao, Yin Quan; Hauck, Paula M.; Shekhar, Anantha; Hao, Chunhai; Pathology and Laboratory Medicine, School of Medicine
    Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.