A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer

Zhang, Tao; Li, Jingjie; He, Yonghong; Yang, Feifei; Huang, Yun; Jin, Wangrui; Wu, Jing; Sun, Zhenliang; Li, Yunqi; Chen, Yi Hua; Yi, Zhengfang; Liu, Mingyao

doi:10.1038/s41467-018-06179-0

Cited by 52 publications

(60 citation statements)

References 41 publications

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“…Tumor metastasis is a multistep process involving metastasis formation and colonization. Approximately one-third of BC patients harbor metastases in lymph nodes at the time of surgery, which highlights the necessity for drugs targeting metastatic colonization 39 . Our work found that NBT impeded BC and LC cell migration and extravasation into the lung parenchyma, thereby revealing a potential capacity to inhibit the formation of metastasis.…”

Section: Discussionmentioning

confidence: 99%

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

Zhang

Zheng

et al. 2019

Cell Death Dis

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Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT-and MBNL2mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

Zhang

Zheng

et al. 2019

Cell Death Dis

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“…Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-related mortality among women worldwide (1,2). Despite the improved prognosis of individuals with BC and advances in radical surgery along with adjuvant therapy (3,4), BC is associated with common recurrence and persistently high mortality rates. BC frequently leads to multi-organ distant metastasis, such as in the lung, bone, liver, and brain (5).…”

Section: Introductionmentioning

confidence: 99%

METTL14 promotes the migration and invasion of breast cancer cells by modulating N6‑methyladenosine and hsa‑miR‑146a‑5p expression

Wang

Shi

et al. 2020

Oncol Rep

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Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. Evidence indicates that posttranscriptional N6-methyladenosine (m6A) modification modulates BC development. In the present study, we assessed BC and normal tissues to investigate this connection. RNA m6A levels were determined by methylation quantification assay. The effects of methyltransferase-like 14 (METTL14) gain-of-expression or co-transfection with an m6A inhibitor on cell migration and invasion abilities were determined by Transwell assays. The levels of differentially expressed (DE) miRNAs were verified by real-time quantitative PCR (RT-qPCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses (KEGG) were performed to analyze potential function of target genes of the DE miRNAs. The effects of candidate miRNAs modulated by METTL14 on cell migration and invasion abilities were confirmed by Transwell assays. We demonstrated that m6A methyltransferase METTL14 was significantly upregulated in BC tissues compared with normal tissues. METTL14 gain-and loss-of-expression regulated m6A levels in MCF-7 and MDA-MB-231 cells. The cell function assays revealed that METTL14 overexpression enhanced the migration and invasion capacities of BC cells. Moreover, treatment with the m6A inhibitor suppressed this enhanced cell migration and invasion. Additionally, aberrant expression of METTL14 reshaped the miRNA profile in BC cell lines. The remodeled DE miRNA/mRNA network was found to be most enriched in cancer pathways, and DE miRNAs were enriched in cell adhesion terms. hsa-miR-146a-5p modulated by METTL14 promoted cell migration and invasion. METTL14 modulates m6A modification and hsa-miR-146a-5p expression, thereby affecting the migration and invasion of breast cancer cells.

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“…Interestingly, mitofusin-2 is a member of the dynamin-like GTPase superfamily and harbors a proline-rich domain [30] when myoferlin contains a SH3 domain [31] controlling protein-protein interactions through proline-rich domains. It is worth noting that a myoferlin colocalization with rab7 GTPase was reported in late endosomes [19], and a direct interaction was suggested in an exogenous expression system [32]. Myoferlin exhibits several additional domains (FerB, FerI, Ferlin C, DysF) with an unidentified function [9], opening new possibilities for its interaction with mitochondrial mitofusins, including mitofusin-1.…”

Section: Discussionmentioning

confidence: 94%

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

Anania

Peiffer

Rademaker

et al. 2020

Cancers

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Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.

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A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer

Cited by 52 publications

References 41 publications

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

METTL14 promotes the migration and invasion of breast cancer cells by modulating N6‑methyladenosine and hsa‑miR‑146a‑5p expression

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

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