HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

Simões-Pires, Cláudia A.; Zwick, Vincent; Nurisso, Alessandra; Schenker, Esther; Carrupt, Pierre Alain; Cuendet, Muriel

doi:10.1186/1750-1326-8-7

Cited by 273 publications

(254 citation statements)

References 122 publications

(169 reference statements)

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“…HDAC6 belongs to group IIb along with HDAC10, and it has unique structural and functional features. 51,52 We also treated cells with an HDAC6 inhibitor, ACY-1215, 53 but found no change in KLF4 expression (not shown). It is very interesting that all four members of Type I HDACs were significantly increased in human lung cancers (Figure 5b and Supplementary Figure 5b).…”

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confidence: 88%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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confidence: 88%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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“…By blocking the interaction between glycosaminoglycans and Sema3A to attenuate Sema3A activity, this peptoid enhances neuronal regrowth in vitro [31][32][33] . Therapeutic inhibition of histone deacetylase-6 (HDAC6) presents promise for neurodegenerative diseases, as evidenced by observations that HDAC6 inhibition rescues impaired axonal transport and HDAC6 knockdown improves function in a mouse model of AD 34,35 . A recent study used rational design to identify a peptoid-based inhibitor of HDAC6.…”

Section: Peptoids As Effectors Of Cell Signalingmentioning

confidence: 99%

Peptoids: Emerging Therapeutics for Neurodegeneration

Moss¹

2017

J Neurol Neuromedicine

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In recent decades, the increasing prevalence of age-associated neurodegenerative diseases has underscored the need for targeted therapeutic strategies and novel diagnostics. Peptide-based neurotherapeutics offer high specificity and tolerability but are limited by proteolytic degradation in vivo. Peptoids, or N-substituted glycines, are versatile peptidomimetics that evade proteolytic degradation yet maintain many qualities that render peptides attractive neurotherapeutic candidates. These molecules may be engineered to their application through modifications that enhance structural stability and reactivity and can withstand various physiological stressors to retain their intended function within anomalous microenvironments.Peptoids generally demonstrate greater cellular permeability than their corresponding peptides, are less immunogenic, and can be administered intranasally, all properties that enhance their potential as neurotherapeutics. Peptoids have primarily been explored as aggregation inhibitors to prevent the deleterious protein plaque deposition associated with several neurodegenerative disorders. However, novel research has uncovered the potential of peptoids toward additional neurotherapeutic applications. Peptoids can modulate cell signaling pathways involved in axonal function and current modulation and can block cell signaling events associated with apoptosis. In addition, these peptidomimetics are able to function as anti-inflammatory agents via multiple mechanisms. Moreover, the versatility and low cost of peptoids render them ideal instruments in biomarker detection, discovery, and imaging. This mini-review explores these diverse applications of peptoids within the context of neurodegenerative disease.

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“…HDAC6 is also involved in ubiquitin-proteosome and lysosomal autophagy-mediated protein aggregate degradation, which is the principal factor for the initiation of many neurodegenerative disorders such as Parkinson's disease (PD) (Lewy bodies) and Alzheimer's disease (AD) (amyloid plaques). HDAC6 appears to be a target in neurodegenerative disorders, and its inhibitor tubacin has potential as a therapeutic alternative [48][49][50].…”

Section: Hdac Class Iibmentioning

confidence: 99%