HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells

Abstract

Cancer stem-like cells (CSCs), a small population of pluripotent cells residing within heterogeneous tumor mass, remain highly resistant to various chemotherapies as compared to the differentiated cancer cells. It is being postulated that CSCs possess unique molecular mechanisms, such as autophagic homeostasis, that allow CSCs to withstand the therapeutic assaults. Here we demonstrate that HDAC6 inhibition differentially modulates macroautophagy/autophagy in CSCs as compared to that of differentiated cancer cells. Using human and murine CSC models and differentiated cells, we show that the inhibition or knockdown (KD) of HDAC6 decreases CSC pluripotency by downregulating major pluripotency factors POU5F1, NANOG and SOX2. This decreased HDAC6 expression increases ACTB, TUBB3 and CSN2 expression and promotes differentiation in CSCs in an apoptosis-independent manner. Mechanistically, HDAC6 KD in CSCs decreases pluripotency by promoting autophagy, whereas the inhibition of pluripotency via retinoic acid treatment, POU5F1 or autophagy-related gene (ATG7 and ATG12) KD in CSCs decreases HDAC6 expression and promotes differentiation. Interestingly, HDAC6 KDmediated CSC growth inhibition is further enhanced in the presence of autophagy inducers Tat-Beclin 1 peptide and rapamycin. In contrast to the results observed in CSCs, HDAC6 KD in differentiated breast cancer cells downregulates autophagy and increases apoptosis. Furthermore, the autophagy regulator p-MTOR, upstream negative regulators of p-MTOR (TSC1 and TSC2) and downstream effectors of p-MTOR (p-RPS6KB and p-EIF4EBP1) are differentially regulated in CSCs versus differentiated cancer cells following HDAC6 KD. Overall these data identify the differential regulation of autophagy as a molecular link behind the differing chemo-susceptibility of CSCs and differentiated cancer cells.

Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma

“…On the contrary, JOC1 increases the expression of differentiation markers TUJ1 and MKP1 in a dosedependent manner. Our current results together with a previous study from our group demonstrating that MKP1 overexpression reduces tumorigenic properties and induces differentiation of GSCs whilst its levels are regulated by HDAC inhibitors 24 , and with another study describing a relationship between HDAC6 activity and SOX2 expression specifically in cancer stem cells 33 , postulate these genes and their underlying pathways as potential mediators of JOC1 activity. In this line, we show that MKP1 overexpressing cells are more sensitive for treatment alone or with TMZ.…”

Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway

“…For example, we could observe phosphorylation of HDAC6 under hypoxia, which was reversed after efficient ATG5 knockdown (data not shown), suggesting that epigenetic modifications might also play a role in the hypoxia-induced phenotype of TICs. Along similar lines, a recent study has highlighted the role of HDAC6 as an important regulator of pluripotency markers and stemness in TICs [ 55 ]. Further research, however, is necessary in order to better unravel the mechanisms that underpin hypoxia-induced self-renewal of TICs.…”

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

“…Towards this purpose, we depleted HDAC11 by siRNAs in A549 and H1650 cells and analyzed the expression of stem cell transcription factors Sox2, Oct4 and Nanog. Additional HDACs like HDAC1 and HDAC6 were also depleted as they were shown to have a role in self-renewal in embryonic stem cells and regulation of Sox2 in cancer respectively 29,30 . Depletion of HDAC1 or HDAC11 resulted in a reduction in the level of Sox2 mRNA in both A549 and H1650 cells (Fig.…”