Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells

Zhang, Shuju; Zhang, Jiaming; Deng, Zhiyuan; Liu, Huadie; Mao, Wei; Jiang, Fang; Xia, Zanxian; Li, Jia‐Da

doi:10.18632/oncotarget.11807

Cited by 19 publications

(15 citation statements)

References 31 publications

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“…SH-SY5Y cells treated with SR1078 exhibited an increase in the expression of RORα target genes (37). MLN4924 may stabilize RORα to suppress proliferation and induce apoptosis in osteosarcoma cells (38). Pantoprazole inhibited the proliferation, self-renewal, and chemoresistance of GC stem cells via the EMT/β-catenin pathway (39); reversed the aggressiveness and EMT marker expression of SGC7901/ADR cells; and suppressed the Wnt/β-catenin pathway (40).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: RORα Suppresses Epithelial-to-Mesenchymal Transition and Invasion in Human Gastric Cancer Cells via the Wnt/β-Catenin Pathway

Xia

et al. 2019

Front. Oncol.

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Retinoid-related orphan receptor alpha (RORα) is involved in tumor development. However, the mechanisms underlying RORα inhibiting epithelial-to-mesenchymal transition (EMT) and invasion are poorly understood in gastric cancer (GC). This study revealed that the decreased expression of RORα is associated with GC development, progression, and prognosis. RORα suppressed cell proliferation, EMT, and invasion in GC cells through inhibition of the Wnt/β-catenin pathway. RORα overexpression resulted in the decreased Wnt1 expression and the increased RORα interaction with β-catenin, which could lead to the decreased intranuclear β-catenin and p-β-catenin levels, concomitant with downregulated T-cell factor-4 (TCF-4) expression and the promoter activity of c-Myc. The inhibition of Wnt/β-catenin pathway was coupled with the reduced expression of Axin, c-Myc, and c-Jun. RORα downregulated vimentin and Snail and upregulated E-cadherin protein levels in vitro and in vivo. Inversely, knockdown of RORα attenuated its inhibitory effects on Wnt/β-catenin pathway and its downstream gene expression, facilitating cell proliferation, EMT, migration, and invasion in GC cells. Therefore, RORα could play a crucial role in repressing GC cell proliferation, EMT, and invasion via downregulating Wnt/β-catenin pathway.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: RORα Suppresses Epithelial-to-Mesenchymal Transition and Invasion in Human Gastric Cancer Cells via the Wnt/β-Catenin Pathway

Xia

et al. 2019

Front. Oncol.

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“…1D). The sensitivity of cancer cells to MLN4924 appeared to be associated with their NAE1 levels, which was consistent with previous reports (15)(16)(17).…”

Section: Mln4924 Inhibits Proliferation Of CML Cells With Nae1 Overexsupporting

confidence: 92%

“…MLN4924 treatment induces apoptosis, DNA damage, and cell-cycle arrest in multiple types of solid and hematopoietic malignant cells (14). Pevonedistat is currently under phase I clinical trials (15,16). Whether neddylation inhibition by MLN4924 induces apoptosis in T315I-BCR-ABL þ cells is elusive.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells

Liu

Nie

et al. 2018

Cancer Research

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Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G-M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34 cells and LSCs in CML-bearing mice via accumulation of p27 in the nucleus. Notably, silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML. These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. .

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“…BMAL1 is a key circadian clock gene that regulates tissue homoeostasis, metabolism and ageing, and it is the only single clock gene knockout in which the experimental animals lose rhythmic behavioural activities 13 . The dysregulation of BMAL1 has been documented in various tumours, such as haematological malignancies 14 , lung cancer 15 , osteosarcoma 16 and PC 17 – 19 . We previously demonstrated that decreased BMAL1 expression in PC suppresses the p53 pathway and significantly enhances tumour growth 19 .…”

Section: Introductionmentioning

confidence: 99%

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

et al. 2018

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Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3′-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a ‘miR-135b–BMAL1–YY1’ loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance.

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Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells

Cited by 19 publications

References 31 publications

RETRACTED: RORα Suppresses Epithelial-to-Mesenchymal Transition and Invasion in Human Gastric Cancer Cells via the Wnt/β-Catenin Pathway

RETRACTED: RORα Suppresses Epithelial-to-Mesenchymal Transition and Invasion in Human Gastric Cancer Cells via the Wnt/β-Catenin Pathway

Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

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