HDAC8 drives spindle organization during meiotic maturation of porcine oocytes

Chen, Ying; Pan, Ci; Lu, Yajuan; Miao, Yun; Xiong, Bo

doi:10.1111/cpr.13119

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…ACY-241 increased the acetylation of α-tubulin and PCI-34051 increased the acetylation of SMC3. PCI-34051 did not cause detectable α-tubulin acetylation when treated alone, as demonstrated in various studies [ 31 , 41 ]. However, combination treatment of ACY-241 and PCI-34051 significantly increased α-tubulin acetylation, suggesting a cooperative role of PCI-34051 in acetylating α-tubulin when treated along with ACY-241.…”

Section: Resultssupporting

confidence: 62%

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

Kim

Han

Yoo

et al. 2022

IJMS

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HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

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Section: Resultssupporting

confidence: 62%

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

Kim

Han

Yoo

et al. 2022

IJMS

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“…In addition, histone deacetylases HDAC8 and HDAC6 have been recently proved to negatively regulate α-tubulin acetylation in mouse oocytes. 47,48 In logic consistence, we found that HDAC6 selective inhibitor tubacin can pronouncedly reverse spindle defects induced by paxillin reduction in SLK-depleted oocytes.…”

Section: Discussionmentioning

confidence: 75%

“…In addition, histone deacetylases HDAC8 and HDAC6 have been recently proved to negatively regulate α‐tubulin acetylation in mouse oocytes. 47 , 48 In logic consistence, we found that HDAC6 selective inhibitor tubacin can pronouncedly reverse spindle defects induced by paxillin reduction in SLK‐depleted oocytes. All the evidence supports that SLK facilitates α‐tubulin acetylation by preserving paxillin at a suitable level, thereby ensuring reasonable microtubule stability for the organizing and maintaining a functionally compete for spindle during oocyte meiotic division.…”

Section: Discussionmentioning

confidence: 77%

Ste20‐like kinase activity promotes meiotic resumption and spindle microtubule stability in mouse oocytes

Song

Jiang

et al. 2022

Cell Proliferation

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Ste20-like kinase (SLK) is involved in cell proliferation and migration in somatic cells.This study aims to explore SLK expression and function in mouse oocyte meiosis.Western blot, immunofluorescence, Co-immunoprecipitation, drug treatment, cRNA construct and in vitro transcription, microinjection of morpholino oilgo (MO) and cRNA were performed in oocytes. High and stable protein expression of SLK was detected in mouse oocyte meiosis, with dynamic distribution in the nucleus, chromosomes and spindle apparatus. SLK phosphorylation emerges around meiotic resumption and reaches a peak during metaphase I (MI) and metaphase II. SLK knockdown with MO or expression of kinase-dead SLK K63R dramatically delays meiotic resumption due to sequentially suppressed phosphorylation of Polo-like kinase 1 (Plk1) and cell division cycle 25C (CDC25C) and dephosphorylation of cyclin-dependent kinase 1 (CDK1). SLK depletion promotes ubiquitination-mediated degradation of paxillin, an antagonist to α-tubulin deacetylation, and thus destroys spindle assembly and chromosome alignment; these phenotypes can be substantially rescued by exogenous expression of SLK kinase active fragment. Additionally, exogenous SLK effectively promotes meiotic progression and spindle assembly in aging oocytes with reduced SLK. Collectively, this study reveals SLK is required for meiotic resumption and spindle assembly in mouse oocyte meiosis. | INTRODUCTIONMammalian oocytes of high-developmental-competence are required for successful fertilization and subsequent embryo development, which initiates a new life. 1 Fully-grown oocytes are arrested at the diplotene stage of the first meiotic prophase, known as the germinal vesicle (GV) stage. 2 Following the ovulatory luteinizing hormone (LH) surge, the resumption of meiosis occurs with the signature of germinal vesicle breakdown (GVBD) followed by chromatin condensation. 3,4 During the prometaphase of meiosis I (Pro-MI), the acentrosomal spindle is assembled along with the congression of condensed chromosomes. 5 Upon all chromosomes are correctly aligned and stably attached by microtubules from spindle poles at metaphase I (MI), the meiotic cell cycle moves to anaphase I (AI), during which the homologous chromosomes are segregated, and the first polar body (PB1) is discharged. 6 The orderly meiotic progression is essential for the high-quality oocytes and, furthermore, female reproductive health. 1,7 The abnormal oocyte meiotic process leads to embryo aneuploidy, a significant cause of infertility, abortion and fetal deformity. 7 The fully-grown oocytes accumulate large quantities of mRNAs and proteins and stop de novo mRNA transcription at the GV stage, so the meiotic progression is regulated by a complex and cascading

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“…The second observation showed that although the pre-pubertal GV oocytes present improved chromatin organization after FSH treatment, once meiosis is resumed it is usually not completed ( Figures 7D–G ). Previous studies on histone acetylation in oocytes showed that de-acetylation is required for proper meiotic segregation ( Ma and Schultz, 2013 ) ( Sui et al, 2020 ) ( Chen et al, 2021 ). Thus, the acetyl-saturated histone profile of pre-pubertal oocytes treated with FSH pattern might present as an obstacle to their meiotic activity.…”

Section: Discussionmentioning

confidence: 99%

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Pash

Karavani

Reich

et al. 2023

Front. Cell Dev. Biol.

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Pre-pubertal oocytes are still dormant. They are arrested in a GV state and do not undergo meiotic divisions naturally. A multitude of molecular pathways are changed and triggered upon initiation of puberty. It is not yet clear which epigenetic events occur in oocytes upon pubertal transition, and how significant these epigenetic events may be. We evaluated epigenetic marker levels in mouse pre-pubertal and post-pubertal female oocytes. In addition, we evaluated H3K9me2 levels in human oocytes collected from fertility preservation patients, comparing the levels between pre-pubertal patients and post-pubertal patients. The chromatin structure shows a lower number of chromocenters in mouse post-pubertal oocytes in comparison to pre-pubertal oocytes. All heterochromatin marker levels checked (H3K9me2, H3K27me3, H4K20me1) significantly rise across the pubertal transition. Euchromatin markers vary in their behavior. While H3K4me3 levels rise with the pubertal transition, H3K27Ac levels decrease with the pubertal transition. Treatment with SRT1720 [histone deacetylase (HDAC) activator] or overexpression of heterochromatin factors does not lead to increased heterochromatin in pre-pubertal oocytes. However, treatment of pre-pubertal oocytes with follicle-stimulating hormone (FSH) for 24 h - changes their chromatin structure to a post-pubertal configuration, lowers the number of chromocenters and elevates their histone methylation levels, showing that hormones play a key role in chromatin regulation of pubertal transition. Our work shows that pubertal transition leads to reorganization of oocyte chromatin and elevation of histone methylation levels, thus advancing oocyte developmental phenotype. These results provide the basis for finding conditions for in-vitro maturation of pre-pubertal oocytes, mainly needed to artificially mature oocytes of young cancer survivors for fertility preservation purposes.

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HDAC8 drives spindle organization during meiotic maturation of porcine oocytes

Cited by 9 publications

References 39 publications

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

Ste20‐like kinase activity promotes meiotic resumption and spindle microtubule stability in mouse oocytes

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

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