Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways

Abstract

Autophagy is a catabolic process in response to starvation or other stress conditions to sustain cellular homeostasis. At present, histone deacetylase inhibitors (HDACIs) are known to induce autophagy in cells through inhibition of mechanistic target of rapamycin (MTOR) pathway. FOXO1, an important transcription factor regulated by AKT, is also known to play a role in autophagy induction. At present, the role of FOXO1 in the HDACIs-induced autophagy has not been reported. In this study, we first observed that HDACIs increased the expression of FOXO1 at the mRNA and protein level. Second, we found that FOXO1 transcriptional activity was enhanced by HDACIs, as evidenced by increased FOXO1 nuclear accumulation and transcriptional activity. Third, suppression of FOXO1 function by siRNA knockdown or by a chemical inhibitor markedly blocked HDACIs-induced autophagy. Moreover, we found that FOXO1-mediated autophagy is achieved via its transcriptional activation, leading to a dual effect on autophagy induction: (i) enhanced expression of autophagy-related (ATG) genes, and (ii) suppression of MTOR via transcription of the SESN3 (sestrin 3) gene. Finally, we found that inhibition of autophagy markedly enhanced HDACIs-mediated cell death, indicating that autophagy serves as an important cell survival mechanism. Taken together, our studies reveal a novel function of FOXO1 in HDACIs-mediated autophagy in human cancer cells and thus support the development of a novel therapeutic strategy by combining HDACIs and autophagy inhibitors in cancer therapy.

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles

“…52,54 Interestingly, the refractoriness to HDACi treatment coincides with the premature block of autophagy reported in this work. Recent evidence underscores a role of HDACi in inducing autophagy 55,56 by directly regulating LC3 levels. The HDACi-mediated induction of autophagy has been associated with ROS and damaged mitochondria clearance that imparts a pro-survival effect.…”

Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?

“…West et al (27) showed that the immune system is absolutely necessary for the anticancer effect of HDACI (9,11,24,28). HDACI distribute to the up-regulation of natural killer NK1-cell activating ligands MHC class I and II, which are responsible for antigen presentation on the surface of cancer cells (22). HDACI can sensitize malignant cells to the antineoplastic effect of IFN-γ by increasing the number of IFN-γ receptors (IFNGR1) on the surface of cancer cells.…”

“…It also increases the expression of Il-2, TNF-a, GM-CSF and the activation of T-cells. Moreover, TSA induces autophagy in cells through inhibition of rapamycin motor pathway (22) and inhibits apoptosis of activated CD4 + T lymphocytes (23). Butyrate as well as trichostatin A inhibited the cell growth mainly by arresting the cell cycle and the cell invasion was inhibited by butyrate and trichostatin A.…”

“…Zhang et al approved that HDACI can enhance FOXO1 acetylation and transcriptional activation by suppressing the action of deacetylases. This way the transcription of ATGs genes increases (autophagy related genes), which are necessary for the autophagy of cancer cells (22).…”

“…Forkhead box proteins (FOXOs) are transcription factors which have an important role in regulation of genes involved in cell growth, proliferation and differentiation, with FOXO1 being the most studied (Autophagy is a mechanism which provides cells with additional nutrient supplies under stress conditions and is mediated by the suppression of rapamycin, MTOR, a negative regulator of autophagy) (22,31). Zhang et al approved that HDACI can enhance FOXO1 acetylation and transcriptional activation by suppressing the action of deacetylases.…”