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HDAC Family Members Intertwined in the Regulation of Autophagy: A Druggable Vulnerability in Aggressive Tumor Entities.

Koeneke E, Witt O, Oehme I - Cells (2015)

Bottom Line: Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors.With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity.Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.

View Article: PubMed Central - PubMed

Affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. e.koeneke@dkfz.de.

ABSTRACT
The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.

No MeSH data available.


Related in: MedlinePlus

Histone deacetylase family members and their inhibitors modulate different phases of the autophagy cascade.
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cells-04-00135-f001: Histone deacetylase family members and their inhibitors modulate different phases of the autophagy cascade.

Mentions: The knockdown of class IIa HDAC4 led to autophagy induction, with increased levels of LC3-II as well as elevated Beclin-1 and ATG7 [82]. Downregulation of HDACs 4 and 5 using miRNA-9* increased total LC3B and Rab7 (marker for late endosomes) expression levels [129]. When HDAC5 was depleted in breast cancer cells, LC3-II increased over time, and this effect was enhanced by the use of a lysosomal inhibitor, indicating that HDAC5 downregulation increased autophagic flux [130]. Thus in most studies, depletion of class I and IIa HDAC isozymes is associated with enhanced expression of autophagy regulators involved in the induction steps (Figure 1A). It is very likely that these HDACs repress important autophagy regulators and that repression is released upon HDAC depletion.


HDAC Family Members Intertwined in the Regulation of Autophagy: A Druggable Vulnerability in Aggressive Tumor Entities.

Koeneke E, Witt O, Oehme I - Cells (2015)

Histone deacetylase family members and their inhibitors modulate different phases of the autophagy cascade.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493453&req=5

cells-04-00135-f001: Histone deacetylase family members and their inhibitors modulate different phases of the autophagy cascade.
Mentions: The knockdown of class IIa HDAC4 led to autophagy induction, with increased levels of LC3-II as well as elevated Beclin-1 and ATG7 [82]. Downregulation of HDACs 4 and 5 using miRNA-9* increased total LC3B and Rab7 (marker for late endosomes) expression levels [129]. When HDAC5 was depleted in breast cancer cells, LC3-II increased over time, and this effect was enhanced by the use of a lysosomal inhibitor, indicating that HDAC5 downregulation increased autophagic flux [130]. Thus in most studies, depletion of class I and IIa HDAC isozymes is associated with enhanced expression of autophagy regulators involved in the induction steps (Figure 1A). It is very likely that these HDACs repress important autophagy regulators and that repression is released upon HDAC depletion.

Bottom Line: Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors.With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity.Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.

View Article: PubMed Central - PubMed

Affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. e.koeneke@dkfz.de.

ABSTRACT
The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.

No MeSH data available.


Related in: MedlinePlus