Role of HDAC5 depletion induced autophagy on cancer cell death

Introduction: Histone deacetylases (HDAC) is a family of eighteen enzymes which modulates the acetylation level of histones and non-histone proteins to regulate gene expression and chromatin structure. Broad spectrum inhibitors of these enzymes can inhibit tumor growth both in vitro and in vivo and are currently used in clinic as anti-cancer agents.
For many years, we are investigating the specific role of individual HDAC members in cancer biology and we have recently demonstrated that depletion of HDAC5 using siRNA technology triggered cancer cells to both autophagy and apoptosis.
The study of autophagy in cancer is a new research field that has recently generated tremendous attention due to the recognition that autophagy can have either pro-survival or pro-death functions depending on its level of activation. In addition, more and more studies indicate that a complex relationship exists between autophagy and apoptosis, and that the interplay between these two processes determines whether a cell will live or die.

- Aims: The aim of this study is to further understand the role of autophagy induced by HDAC5 depletion. Current investigations include determining the molecular mechanisms of HDAC5 depletion-mediated autophagy and exploring regulatory relationships between autophagy and apoptosis on cancer cell death in absence of HDAC5.

- Methods and results :
The set up of the autophagy in absence of HDAC5 occurs trough a non-canonical pathway which depends on the JNK activation. This activation could be induced by an inappropriate ROS production. Indeed, a transcriptomic analysis performed in HDAC5 depleted Hela cells highlighted a deregulation of a set of genes implicated in ROS detoxification. This deregulation has been validated by FACS analysis.

- Conclusion: Through this study we determined the molecular mechanism implicated in the autophagy induction after HDAC5 silencing. This phenomenon appears dependent of an accumulation of ROS into the cells that activates JNK and mediate cell death by autophagy and apoptosis. Now, in we hope to determine whether manipulation of autophagy may provide a useful way to increase the efficacy of treatments with HDAC inhibitors, and limit tumor progression.