HDAC6 inhibition induces the failure of mouse early embryonic development

Abstract

Histone deacetylases (HDACs) have been implicated in numerous biological events. However, to date, the role of HDAC6 in early embryos remains unknown. In the current study, Tubastatin A (TubA), a potent HDAC6 inhibitor, was used to block HDAC6 activity in mouse embryos. We found that TubA exposure significantly reduced the blastocyst formation of early embryos. Confocal microscopy revealed the markedly increased chromosomal congression failure in the mouse embryos treated with the HDAC6 inhibitor. Moreover, the HDAC6 inhibition resulted in the overproduction of reactive oxygen species (ROS) in embryos. In addition, we observed the accumulation of phosphorylated γH2AX in TubA‐treated embryos, indicative of the increased DNA damage. In line with this, cell apoptosis of blastocysts was frequently detected in HDAC6‐deficient embryos compared with their controls. Altogether, our data indicate that HDAC6 may serve as an important regulator of chromatin structure and mitochondrial function, determining the developmental potential of the early embryos of mouse.

Pharmacological inhibition of HDAC6 overcomes cisplatin chemoresistance by targeting cancer stem cells in oral squamous cell carcinoma

“…26 Although there is a lack of information about the effect of tubastatin A on ROS accumulation in tumors, the inhibition of HDAC6 by tubastatin A resulted in increased ROS production and phospho-H2A.X in mouse early embryos. 27 It agrees with our results, demonstrating that tubastatin A efficiently increased both ROS and phospho-H2A.X levels in cisplatin-resistant CSCs and strongly increased phospho-H2A.X when combined with cisplatin. The administration of Tubacin, one of the first HDAC6 inhibitors developed, resulted in increased H2A.X in glioma CSCs, suggesting the DNA repair capacity can be reduced by inhibiting HDAC6.…”

“…Cancer stem cells present high antioxidant enzymes production and lower ROS accumulation, conferring greater resistance to therapy 26 . Although there is a lack of information about the effect of tubastatin A on ROS accumulation in tumors, the inhibition of HDAC6 by tubastatin A resulted in increased ROS production and phospho‐H2A.X in mouse early embryos 27 . It agrees with our results, demonstrating that tubastatin A efficiently increased both ROS and phospho‐H2A.X levels in cisplatin‐resistant CSCs and strongly increased phospho‐H2A.X when combined with cisplatin.…”

Role of HDAC6 inhibition in sepsis‑induced acute respiratory distress syndrome (Review)

“…In addition, the inhibition of HDAC6 induced an excessive production of ROS. An increase in the accumulation of phosphorylated γ-H2AX was also observed in the embryos after TubA intervention indicating an increase in DNA damage and blastocyst cell apoptosis (89). TubA interfered with and halted mouse oocyte meiosis by regulating several key histones (H4K16 acetylation and h3t3 and H3S10 phosphorylation) and messenger RNA (ccnb1, CDK2, Smad3 and YWHAZ methylation-associated genes DNMT1 and DNMT3b), and by interfering with the organization of spindles of chromosomes, as well as the attachment of mitotic microtubules.…”

Advances in the Mechanistic Study of the Control of Oxidative Stress Injury by Modulating HDAC6 Activity

“…In addition to cancer cells, HDAC6 inhibition induces oxidative stress injury in other types of cells. Treatment of fertilized mouse oocytes and embryos with tubastatin A increased ROS levels, suggesting that HDAC6 regulates redox homeostasis in mouse embryos [ 130 ]. In mesenchymal stem cells (MSCs), HDAC6 knockout promotes the acetylation of lysine (K) 120 in p53, significantly damaging mitochondrial respiration and increasing ROS [ 81 ].…”