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1.
Nucleic Acids Res ; 51(15): 7951-7971, 2023 08 25.
Article in English | MEDLINE | ID: mdl-37395406

ABSTRACT

The fidelity of alternative splicing (AS) patterns is essential for growth development and cell fate determination. However, the scope of the molecular switches that regulate AS remains largely unexplored. Here we show that MEN1 is a previously unknown splicing regulatory factor. MEN1 deletion resulted in reprogramming of AS patterns in mouse lung tissue and human lung cancer cells, suggesting that MEN1 has a general function in regulating alternative precursor mRNA splicing. MEN1 altered exon skipping and the abundance of mRNA splicing isoforms of certain genes with suboptimal splice sites. Chromatin immunoprecipitation and chromosome walking assays revealed that MEN1 favored the accumulation of RNA polymerase II (Pol II) in regions encoding variant exons. Our data suggest that MEN1 regulates AS by slowing the Pol II elongation rate and that defects in these processes trigger R-loop formation, DNA damage accumulation and genome instability. Furthermore, we identified 28 MEN1-regulated exon-skipping events in lung cancer cells that were closely correlated with survival in patients with lung adenocarcinoma, and MEN1 deficiency sensitized lung cancer cells to splicing inhibitors. Collectively, these findings led to the identification of a novel biological role for menin in maintaining AS homeostasis and link this role to the regulation of cancer cell behavior.


Subject(s)
Alternative Splicing , Lung Neoplasms , Animals , Humans , Mice , Alternative Splicing/genetics , Genomic Instability/genetics , Lung Neoplasms/genetics , R-Loop Structures , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA, Messenger/metabolism
2.
Cell Death Dis ; 13(11): 967, 2022 11 18.
Article in English | MEDLINE | ID: mdl-36400758

ABSTRACT

Long noncoding RNAs (lncRNAs) are a novel class of noncoding RNAs that have emerged as critical regulators and biomarkers in various cancers. Nevertheless, the expression profile and mechanistic function of lncRNAs in cholangiocarcinoma (CCA) remain unclear. Herein, we examined the expression levels of linc00976 in clinical specimens and cell lines using reverse transcription-quantitative PCR. In total, 50 patients with CCA were enrolled to analyze the correlation between linc00976 expression and clinical characteristics of CCA. Loss- and gain-of-function experiments were performed to investigate the biological effects of linc00976 on proliferation, ferroptosis, migration, and invasion of CCA cells in vitro and in vivo. In situ hybridization, RNA immunoprecipitation, bioinformatic databases, RNA pull-down assay, a dual-luciferase reporter assay, mRNA sequencing, chromatin immunoprecipitation-PCR, and rescue experiments were performed to elucidate the underlying mechanisms of linc00976-induced competitive endogenous RNA regulatory networks. We characterized a novel and abundant lncRNA, linc00976, that functions as a pro-oncogenic regulator of CCA progression. Compared with normal controls, linc00976 was dramatically upregulated in CCA tissue samples and cell lines. Patients with CCA exhibiting high linc00976 expression had a highly advanced clinical stage, substantial lymph node metastasis, and poor overall survival. Knockdown of linc00976 significantly repressed proliferation and metastasis and promoted ferroptosis of CCA cells both in vitro and in vivo, whereas linc00976 overexpression exerted the opposite effect. Mechanistically, linc00976 competitively interacted with miR-3202 to upregulate GPX4 expression, thus contributing to the malignant biological behavior of CCA cells. Moreover, we demonstrated that JUND specifically interacts with the linc00976 promoter and activates linc00976 transcription. Accordingly, JUND promotes linc00976 transcription, and linc00976 plays a crucial role in accelerating CCA tumorigenesis and metastasis and inhibiting ferroptosis by modulating the miR-3202/GPX4 axis. These findings suggest that targeting linc00976 may afford a promising therapeutic strategy for patients with CCA.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Ferroptosis , MicroRNAs , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Ferroptosis/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Gene Expression Regulation, Neoplastic/genetics , Cell Proliferation/genetics , Cell Line, Tumor , Cholangiocarcinoma/pathology , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Proto-Oncogene Proteins c-jun/metabolism
3.
Bioengineered ; 13(5): 12193-12210, 2022 05.
Article in English | MEDLINE | ID: mdl-35549979

ABSTRACT

Hypoxia environment exists in already started hepatocellular carcinoma (HCC) and promotes its progression by driving changes in the gene expression profiles of cells. However, the status of hypoxia-driven genes in HCC is largely unknown. In the present study, 368 HCC tissues from The Cancer Genome Atlas were divided into high and low hypoxia groups according to their hypoxia signatures. A total of 1,142 differentially expressed genes (DEGs) were identified between the two groups, and 34 of these DEGs were highly expressed in HCC tissues compared with adjacent tissues, especially in HCC tissues from patients with stage III-IV HCC. After constructing a protein-protein interaction network and applying the least absolute shrinkage and selection operator Cox regression method for 34 DEGs, a three-gene signature (complement factor H related 3 [CFHR3], egl-9 family hypoxia inducible factor 3 [EGLN3], and chromogranin A [CHGA]) was constructed and had prognostic value to predicted outcome of patients with HCC. This three-gene signature was suitable for classifying patients with HCC in the International Cancer Genome Consortium. CFHR3 shows remarkable diagnostic value in HCC. Hypoxia decreased CFHR3 expression, but increased HCC cell proliferation and motility. Overexpression of CFHR3 in HCC cells under hypoxia reversed the stimulatory effects of hypoxia and suppressed cell proliferation and metastasis in vivo. In conclusion, we identified a novel hypoxia-driven gene signature (CFHR3, EGLN3, and CHGA) for reliable prognostic prediction of HCC, and demonstrated that overexpression of CFHR3 may be a potential strategy to overcome hypoxia and treat HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/metabolism , Gene Expression Profiling , Humans , Hypoxia/genetics , Liver Neoplasms/metabolism , Prognosis
4.
Biochem Pharmacol ; 154: 255-264, 2018 08.
Article in English | MEDLINE | ID: mdl-29753750

ABSTRACT

Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). With significantly improved water solubility, S222 and S439 displayed 12- and 14-times more potent proliferative inhibition than their parent tanshinone-1 in a panel of 15 cancer cell lines. Both retained tanshinone-1's anti-MDR and anti-angiogenesis properties and its capability to reduce the phosphorylation of Stat3 at Tyr705 with apparently enhanced efficacy and in these regards, S439 was also slightly more potent than S222. Both derivatives and tanshinone-1 directly inhibited Top1 and Top2 at molecular and cellular levels; the derivatives displayed similar potency but both were more potent than tanshinone-1. The inhibition of S222 and S439 on Top1 and Top2 was also more potent than that of the Top1 inhibitor hydroxylcamptothecin and the Top2 inhibitor etoposide, respectively. Consistently, tanshinone-1 and its derivatives induced DNA double-strand breaks, G2/M arrest and apoptosis. Unexpectedly, the derivatives demonstrated different p53-dependency in inducing both cell cycle arrest and apoptosis. S222 showed no obvious p53-dependency. In contrast, S439 induced more G2/M arrest in p53-proficient cells than in p53-deficient cells while its apoptotic induction was the opposite. However, their proliferative inhibition was independent of the p53 status. Due to their structures different from the known Top1, Top2 and dual Top1/2 inhibitors, our results indicate that tanshinone-1 and its derivatives are a new type of dual Top1/2 inhibitors.


Subject(s)
Abietanes/pharmacology , Apoptosis/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Genes, p53/drug effects , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/pharmacology , A549 Cells , Abietanes/chemistry , Apoptosis/physiology , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/physiology , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Dose-Response Relationship, Drug , G2 Phase Cell Cycle Checkpoints/physiology , Genes, p53/physiology , HCT116 Cells , Humans , K562 Cells , MCF-7 Cells , Topoisomerase I Inhibitors/chemistry , Topoisomerase II Inhibitors/chemistry
5.
J Med Chem ; 61(3): 760-776, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29294282

ABSTRACT

The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice.


Subject(s)
Abietanes/chemistry , Abietanes/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Discovery , Nitrogen/chemistry , Abietanes/pharmacokinetics , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Humans , Male , Mice , Poly(ADP-ribose) Polymerases/metabolism , Solubility , Tissue Distribution , Xenograft Model Antitumor Assays
6.
Oncotarget ; 6(11): 8960-73, 2015 Apr 20.
Article in English | MEDLINE | ID: mdl-25840421

ABSTRACT

Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 µM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.


Subject(s)
Carbolines/therapeutic use , DNA Breaks, Double-Stranded/drug effects , DNA, Neoplasm/drug effects , Neoplasm Proteins/antagonists & inhibitors , Topoisomerase II Inhibitors/therapeutic use , Tubulin Modulators/therapeutic use , Animals , Apoptosis/drug effects , Binding Sites/drug effects , Binding, Competitive , Carbolines/pharmacology , Cell Line, Tumor , Colchicine/metabolism , Colonic Neoplasms/drug therapy , DNA Topoisomerases, Type II/physiology , DNA, Superhelical/drug effects , Drug Interactions , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Humans , Inhibitory Concentration 50 , Metaphase/drug effects , Mice , Mice, Nude , Microtubules/drug effects , Microtubules/metabolism , Molecular Structure , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/physiology , Paclitaxel/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Vincristine/pharmacology
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