MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer

Bae, Hyun Jin; Jung, Kwang Hwa; Eun, Jung Woo; Shen, Qingyu; Kim, Hyung Seok; Park, Se Jin; Shin, Woo Chan; Yang, Hee Doo; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

doi:10.1016/j.jhep.2015.03.019

Cited by 84 publications

(72 citation statements)

References 36 publications

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“…A regulatory link between miR-221 and Beclin-1 has been suggested, since Beclin-1 is regulated by HDAC6 (35) and HDAC6 is regulated by miR-221 (36). Additionally, a regulatory role of mda-7/IL-24 in toxic autophagy has been described (37).…”

Section: Resultsmentioning

confidence: 99%

“…Beclin-1-mediated protective/toxic autophagy, depending on cellular context, plays a decisive role in cell survival/death and aberrant expression of beclin-1 has been reported in different diseases including cancer (26, 46–49). Rapamycin is a well described autophagy inducer (50) and it also up regulates beclin-1 (36). Our results confirm that miR-221 not only degrades basal but also Rapamycin- and mda-7/IL-24 -induced beclin-1 expression.…”

Section: Discussionmentioning

confidence: 99%

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mda-7/IL-24 Mediates Cancer Cell–Specific Death via Regulation of miR-221 and the Beclin-1 Axis

et al. 2017

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Melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) displays broad-spectrum anti-cancer activity in vitro, in vivo in preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate that mda-7/IL-24 regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression of mda-7/IL-24 or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death. Mda-7/IL-24-induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, and mda-7/IL-24 regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221 overexpressing MDA-MB-231 clones were more aggressive and resistant to mda-7/IL-24-mediated cell death than parental clones. This is the first demonstration that mda-7/IL-24 directly regulates microRNA expression in cancer cells and highlights the novelty of the mda-7/IL-24-miR-221-beclin-1 loop in mediating cancer cell-specific death.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mda-7/IL-24 Mediates Cancer Cell–Specific Death via Regulation of miR-221 and the Beclin-1 Axis

et al. 2017

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“…TS KI4 cells are in an intermediate state of EMT, suggesting an explanation for elevated HDAC6 transcript and protein (Abell et al, 2011). Alternatively, MAP3K4 may repress HDAC6 transcripts through the regulation of MAPK-dependent transcription factors or AP1 controlled microRNAs (Bae et al, 2015). In addition, HDAC6 inhibition with tubastatin decreased HDAC6 transcript levels, suggesting that HDAC6 may regulate its own expression.…”

Section: Discussionmentioning

confidence: 99%

MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition

et al. 2017

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SUMMARY The first epithelial to mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships between MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TSKI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TSKI4 cells restores epithelial features including cell-cell adhesion and barrier formation. These data define an epigenetic role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes.

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“…For instance, hypoxia-responsive miR-26a directly targets the 3¢ UTR of the HDAC6 gene and suppresses HDAC6 expression, leading to the acetylation of histones and finally embryonic stem cell differentiation [55]. Other than miR-26, the activity or expression of HDAC6 is also downregulated by miR-433, miR-221, miR-22 and miR-548m, which, in turn, causes tumour cell growth and metastasis [56][57][58][59][60].…”

Section: Sam68mentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

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Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and b-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylaseand ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.

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MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer

Cited by 84 publications

References 36 publications

mda-7/IL-24 Mediates Cancer Cell–Specific Death via Regulation of miR-221 and the Beclin-1 Axis

mda-7/IL-24 Mediates Cancer Cell–Specific Death via Regulation of miR-221 and the Beclin-1 Axis

MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition

Cellular defence or viral assist: the dilemma of HDAC6

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