KAT8‐Low Osteosarcoma Suppresses Cisplatin Sensitivity via H4K16ac‐Mediated Cell Apoptosis

The KAT8-CDK1 K33 acetylation axis drives doxorubicin resistance by suppressing ferroptosis and apoptosis in breast cancer

Doxorubicin (Dox) resistance severely limits therapeutic efficacy in breast cancer, yet the epigenetic mechanisms linking cell-cycle control to therapy-induced cell death remain unclear. Here, we identify the histone acetyltransferase KAT8 as a critical driver of Dox resistance. Transcriptomic analysis of neoadjuvant cohorts revealed elevated KAT8 expression in residual disease (RD) tumors, which was validated in an independent cohort of 95 patients. High KAT8 levels correlated with poor therapeutic response. Mechanistically, KAT8 directly acetylated CDK1 at lysine 33 (K33) in Dox-resistant MCF-7/ADR and MDA-MB-231/ADR cells. K33 acetylation sustained CDK1 phosphorylation at T14, Y15, and T161, maintaining kinase activity under chemotherapeutic stress. Disruption of KAT8, either by genetic silencing or pharmacological inhibition with MG149, reduced CDK1 activation, increased mitochondrial depolarization and oxidative stress, and restored Dox sensitivity. Functionally, KAT8-dependent CDK1 K33 acetylation suppressed both apoptosis and ferroptosis, two principal Dox-induced cell death pathways. Re-expression of wild-type CDK1, but not the acetylation-deficient K33R mutant, rescued chemoresistance. In vivo, MG149 co-treatment or expression of CDK1-K33R significantly enhanced Dox-mediated tumor suppression in xenograft models without overt toxicity. Together, these findings establish KAT8-dependent CDK1 K33 acetylation as a key epigenetic mechanism sustaining anthracycline resistance and suggest that targeting the KAT8-CDK1 axis may provide a therapeutic strategy to overcome refractory breast cancer.

RMI2 knockdown suppresses ovarian cancer cell growth by impairing DNA damage repair via the ATR/CHK1 signaling pathway.

HDAC2‐Mediated SMAD7 Stabilisation Activates Wnt/β‐Catenin Signalling to Drive DNA Damage Repair and Cisplatin Resistance in Ovarian Cancer

To investigate the role of histone deacetylase 2 (HDAC2) in cisplatin resistance in ovarian cancer (OC). Cisplatin‐resistant OC cell lines were employed to construct HDAC2 overexpression and knockdown models, and their effects on cell proliferation and apoptosis were examined. Chromatin immunoprecipitation, immunoprecipitation, and dual‐luciferase reporter assays were performed to investigate the regulation of SMAD7 protein stability and promoter activity by HDAC2. Expression of DNA damage repair‐related genes was detected by qRT‐PCR. A xenograft mouse model was established for in vivo validation. HDAC2 was highly expressed in cisplatin‐resistant OC cells. Overexpression of HDAC2 enhanced drug resistance and inhibited apoptosis and DNA damage, whereas knockdown of HDAC2 exhibited the opposite effects. Mechanistically, HDAC2 directly deacetylated the SMAD7 protein to prevent its degradation rather than suppressing its transcription via H3K27 deacetylation. The HDAC2/SMAD7 axis promoted drug resistance by activating the Wnt/β‐catenin signalling pathway and modulating DNA damage repair‐related genes. In vivo experiments confirmed that HDAC2 knockdown significantly inhibited tumour growth and enhanced the sensitivity. HDAC2 enhances cisplatin resistance in OC by deacetylating and stabilising SMAD7 protein, thereby activating the Wnt/β‐catenin signalling pathway and promoting DNA damage repair.

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple‐Negative Breast Cancer to Doxorubicin

ABSTRACT Doxorubicin remains an important component of chemotherapy for triple‐negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin‐treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1–SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN‐induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin‐mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

TET1 Inhibition Promotes Therapeutic Sensitivity in TP53‐Mutant GBM by Influencing Genome Fragility and Altering TAMs Biology

ABSTRACT TP53 mutations (TP53mut) are associated with therapeutic resistance in glioblastoma (GBM) patients, yet the underlying mechanisms remain incompletely understood. Here, we identified an association between reduced P53 function and increased expression of the epigenetic regulator TET1 in GBM models. In TP53mut GBM cells, TET1 knockdown influenced genome fragility, including DNA damage, senescence, and telomere shortening. Specifically, our findings are consistent with a model in which TET1 binds to the ROS1 promoter and may help maintain ROS1 expression, likely by keeping the promoter in a hypomethylated state, along with downstream ERK phosphorylation. Conversely, inhibiting TET1 correlates with reduced ROS1 expression, attenuation of ERK signaling, and increased genome fragility. Furthermore, TET1 depletion in tumor cells was associated with altered tumor‐associated macrophages biology both in vitro and in vivo, including increased infiltration, differentiation, M1‐like polarization, and phagocytic capacity. Notably, combining the TET1 inhibitor Bobcat339 with cisplatin synergistically inhibited TP53mut GBM growth in vitro and in vivo, improving survival without significant toxicity. Our findings suggest that TET1 may serve as a potential mediator of therapy resistance and a promising therapeutic target in TP53mut GBM.

HMGB2 Impacts Cisplatin-Induced DNA Adduct Processing in Chemoresistant Ovarian Cancer Cells

Background/Objectives: Cisplatin is used in the treatment of ovarian cancer; however, the development of resistance, often due to the efficient repair of cisplatin-induced DNA damage, remains a major barrier to effective therapy. Among these lesions, DNA interstrand crosslinks (ICLs) are particularly cytotoxic because they prevent DNA replication and transcription. HMGB2, a member of the high-mobility group box (HMGB) protein family, can bind DNA lesions and has been implicated in genome maintenance and DNA repair. This study investigated whether HMGB2 contributes to the processing of cisplatin-induced DNA damage and modulates cisplatin sensitivity in human ovarian cancer cells. Methods: HMGB2 expression was suppressed by siRNA in cisplatin-sensitive A2780 and cisplatin-resistant CP70 human ovarian cancer cells. Cellular responses to cisplatin were assessed using clonogenic survival assays, cell cycle analysis, Western blotting, slot blot analysis, and modified alkaline comet assays. Results: HMGB2 depletion reduced clonogenic survival in cisplatin-resistant CP70 cells and increased the sub-G1 population, indicating enhanced apoptotic DNA fragmentation following cisplatin treatment in both cell lines. Depletion of HMGB2 resulted in increased persistence of cisplatin–DNA adducts and impaired ICL processing, as demonstrated by persistent DNA damage over time and reduced ICL unhooking efficiency. DNA damage response signaling following cisplatin treatment was also altered by HMGB2 depletion in both cell lines, whereas the expression levels of key DNA repair proteins were unchanged. Conclusions: Our findings demonstrate that HMGB2 is involved in the cellular response to cisplatin treatment by promoting the efficient processing of cisplatin DNA adducts, particularly ICLs, thereby modulating cisplatin sensitivity in human ovarian cancer cells. These findings suggest that targeting HMGB2 may serve as a potential therapeutic strategy for overcoming cisplatin resistance in ovarian cancer.