Nian‐Kang Sun

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

AbstractMore than 90% of ovarian cancer deaths are due to relapse following development of chemoresistance. Our main objective is to better understand the molecular mechanism underlying paclitaxel resistance (taxol resistance, Txr) in ovarian cancer. Here, we observed that the linker histone H1.0 is upregulated in paclitaxel‐resistant ovarian cancer cells. Knockdown of H1.0 significantly downregulates the androgen receptor (AR) and sensitizes paclitaxel‐resistant SKOV3/Txr and 2774/Txr cell lines to paclitaxel. Conversely, ectopic expression of H1.0 upregulates AR and increases Txr in parental SKOV3 and MDAH2774 cells. Notably, H1.0 upregulation is associated with disease recurrence and poor survival in a subset of ovarian cancer subjects. Inhibition of PI3K significantly reduces H1.0 mRNA and protein levels in paclitaxel‐resistant cells, suggesting the involvement of the PI3K/AKT signaling pathway. Knockdown of H1.0 and AR also downregulates the Txr genes ABCB1 and ABCG2 in paclitaxel‐resistant cells. Our data show that H1.0 induces GCN5 expression and histone acetylation, thereby enhancing Txr gene transactivation. These findings suggest that Txr in ovarian cancer involves the PI3K/AKT pathway and leads to upregulation of histone H1.0, recruitment of GCN5 and AR, followed by upregulation of a subgroup of Txr genes that include ABCB1 and ABCG2. This study is the first report describing the relationship between histone H1.0 and GCN5 that cooperate to induce AR‐dependent Txr in ovarian cancer cells.

H1.0 modulates IL-6 expression and paclitaxel resistance via HDAC5 in ovarian cancer cells

Chemoresistance is a significant challenge and major obstacle to achieving cancer remission during chemotherapy, primarily due to the risk of recurrence and metastasis. This study reveals that linker histone H1.0 plays a crucial role in paclitaxel resistance (TXR) in ovarian cancer cells by regulating Histone deacetylase 5 (HDAC5), which deacetylates core histones and represses gene transactivation. Transcriptomic profile analysis revealed that cytokine signaling networks are enriched pathways that correlate with H1.0 expression. Advanced clustering analysis identified interleukin 6 (IL-6) as a key molecule connecting these enriched H1.0-related pathways. Furthermore, gain- and loss-of-H1.0 expression experiments showed that H1.0 controls IL-6 mRNA and protein expression in ovarian cancer cells. Additionally, our findings indicate that HDAC5 expression is downregulated in SKOV3/Txr cells compared with parental cells. H1.0 silencing in TXR cells increases HDAC5 levels, suggesting an antagonistic effect between H1.0 and HDAC5. Cell viability assays showed that HDAC5 overexpression markedly inhibited cell survival. Furthermore, ectopic HDAC5 overexpression reduced IL-6 mRNA and protein expression, which was increased by H1.0. This effect was associated with reduced H3K9Ac core histone acetylation and decreased NF-κB binding on the IL-6 promoter, as demonstrated by chromatin immunoprecipitation assays. Further analysis revealed that HDAC5 is downregulated in several tumor types. Furthermore, high H1.0 and IL-6 expression, coupled with low HDAC5 levels, was exclusively observed in ovarian carcinoma. Together, our results demonstrate an interplay between H1.0, HDAC5, and IL-6 in modulating paclitaxel resistance in ovarian cancer cells, highlighting new therapeutic targets to overcome chemoresistance.