Histone deacetylases in hearing loss: Current perspectives for therapy

Chen, Daishi; Xu, Ming; Wu, Beibei; Chen, Lei

doi:10.1016/j.joto.2017.04.002

Cited by 6 publications

(7 citation statements)

References 96 publications

(125 reference statements)

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“…Furthermore, SIRT inhibitor administration activates the proapoptotic protein, an upstream mediator of mitochondrial membrane disruption, through the overexpression of antiapoptotic Bcl-2, which is known to be downregulated by SIRT expression [ 23 , 24 ]. Previous studies have indicated that modifications to the histone proteins are associated with the tumorigenesis of endometrial cancer development [ 25 , 26 , 27 ]. However, a dual function of SIRT1 in tumor promotion and suppression has been described in different cancer types [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

Son

Sachan

et al. 2018

IJMS

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We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. A detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced the number of cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

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Section: Discussionmentioning

confidence: 99%

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

Son

Sachan

et al. 2018

IJMS

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show abstract

“…activates the proapoptotic protein, an upstream mediator of mitochondrial membrane disruption, through overexpression of antiapoptotic Bcl-2, which is known to be down-regulated by SIRT expression [23,24]. Previous studies indicated that modifications in histone proteins are associated with the tumorigenesis of endometrial cancer development [25][26][27]. However, a dual function of SIRT1 in tumor promotion and suppression has been described in different cancer types [28,29].…”

Section: Mhy2256 Induces Autophagic Cell Deathmentioning

confidence: 99%

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

Son

Sachan

et al. 2018

Preprint

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We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

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“…NF-κB is a transcription factor that regulates the expression of a variety of genes involved in inflammation and immunity. 81 , 104 , 105 Sodium butyrate is a well-documented HDAC inhibitor 18 , 27 , 54 , 101 , 105 that has demonstrated anti-inflammatory NF-κB inhibition properties. 50 , 101–105 Butyrate mediates NF-κB activation by rescuing the redox machinery and controlling reactive oxygen species 105 that are highly injurious to hair cells 18 , 132 by suppressing the NF-κB signaling pathways.…”

Section: α-Lipoic Acid L -Carnitine and Butyratementioning

confidence: 99%

“… 10 Irreversible hearing loss can also be the product of disease 12 , 16 , 23 , 24 and is often an unfortunate side effect of the aminoglycoside antibiotics 25–30 and platin-based anticancer drugs. 10 , 27 , 28 , 30–36 Regrettably, once damage has occurred, hearing aids and cochlear implantation are the only compensatory options presently available for affected individuals. 37 …”

Section: Introductionmentioning

confidence: 99%

A New Approach to Treating Neurodegenerative Otologic Disorders

Moos

Faller

Glavas

et al. 2018

BioResearch Open Access

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Hearing loss, the most common neurological disorder and the fourth leading cause of years lived with disability, can have profound effects on quality of life. The impact of this “invisible disability,” with significant consequences, economic and personal, is most substantial in low- and middle-income countries, where >80% of affected people live. Given the importance of hearing for communication, enjoyment, and safety, with up to 500 million affected globally at a cost of nearly $800 billion/year, research on new approaches toward prevention and treatment is attracting increased attention. The consequences of noise pollution are largely preventable, but irreversible hearing loss can result from aging, disease, or drug side effects. Once damage occurs, treatment relies on hearing aids and cochlear implants. Preventing, delaying, or reducing some degree of hearing loss may be possible by avoiding excessive noise and addressing major contributory factors such as cardiovascular risk. However, given the magnitude of the problem, these interventions alone are unlikely to be sufficient. Recent advances in understanding principal mechanisms that govern hearing function, together with new drug discovery paradigms designed to identify efficacious therapies, bode well for pharmaceutical intervention. This review surveys various causes of loss of auditory function and discusses potential neurological underpinnings, including mitochondrial dysfunction. Mitochondria mitigate cell protection, survival, and function and may succumb to cumulative degradation of energy production and performance; the end result is cell death. Energy-demanding neurons and vestibulocochlear hair cells are vulnerable to mitochondrial dysfunction, and hearing impairment and deafness are characteristic of neurodegenerative mitochondrial disease phenotypes. Beyond acting as cellular powerhouses, mitochondria regulate immune responses to infections, and studies of this phenomenon have aided in identifying nuclear factor kappa B and nuclear factor erythroid 2-related factor 2/antioxidant response element signaling as targets for discovery of otologic drugs, respectively, suppressing or upregulating these pathways. Treatment with free radical scavenging antioxidants is one therapeutic approach, with lipoic acid and corresponding carnitine esters exhibiting improved biodistribution and other features showing promise. These compounds are also histone deacetylase (HDAC) inhibitors, adding epigenetic modulation to the mechanistic milieu through which they act. These data suggest that new drugs targeting mitochondrial dysfunction and modulating epigenetic pathways via HDAC inhibition or other mechanisms hold great promise.

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Histone deacetylases in hearing loss: Current perspectives for therapy

Cited by 6 publications

References 96 publications

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

A New Approach to Treating Neurodegenerative Otologic Disorders

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