时间标签：数据日期 2026-11-05 · 生成时间 2026-11-05 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/11/02 – 2026/11/06 ｜ 情报发生日期 2026-11-05
研究问题
In this tissue, HOXA10 expression is associated with organogenesis and a differentiated cell state, highlighting cell type-specific functions.23Here we investigated the functional and epigenetic features associated with the coordinated overexpression and repression of the stem cell-related HOX signature observed in GB-derived sphere lines (GS) upon perturbation with the BETi JQ1.；This signature is enriched for HOXA genes, comprising, but not limited to, HOXA3, HOXA5, HOXA7, HOXA9, and HOXA10, together with HOXC6, HOXD3, HOXD8, HOXD10, and the stem cell marker Prominin 1 (PROM1, CD133).16 Gene Set Enrichment Analysis (GSEA) against the GB-derived molecular signatures from Murat et al16 revealed a significant negative enrichment score for the core HOX signature (G28, P-adjusted ≤.001) following JQ1 treatment (Figure S1B).To place these transcriptional effects into their epigenetic context, we investigated the epigenetic landscape with focus on the HOXA region on CHR 7.；HOXA10 Knockdown Is Associated With the Repression of Other HOXA GenesIntrigued by the coordinated repression of HOXA gene cluster expression by BETi in high-HOX GS lines, we investigated whether targeting an individual gene within the locus would affect cluster-wide expression.
方法
Here we report on the identification of epigenetic vulnerabilities that may be leveraged in combination therapies.；Disturbing GB-derived stem-like cells with epigenetic drugs, we uncovered that a HOXA gene dominated hematopoietic stem cell-related signature, previously associated with aggressiveness and treatment resistance, can be repressed in a coordinated manner, resulting in loss of stem cell features.；In this tissue, HOXA10 expression is associated with organogenesis and a differentiated cell state, highlighting cell type-specific functions.23Here we investigated the functional and epigenetic features associated with the coordinated overexpression and repression of the stem cell-related HOX signature observed in GB-derived sphere lines (GS) upon perturbation with the BETi JQ1.
核心结论
Building on these observations, Kurscheid et al19 demonstrated that coordinated HOX gene expression in GB was tightly linked to locus-specific DNA methylation patterns, associated with gain of chromosome 7 (CHR 7), a characteristic feature of GB.；This aligns with Crump et al,46 who reported that BETi disrupts transcription while enhancer-promoter contacts remain intact, concluding that these are separable events and that high-level BRD4 binding is not required to maintain these interactions.；Current efforts aim to identify higher-order structural epigenetic alterations (3D), including compartment switching, that may give rise to new interactions and uncover druggable vulnerabilities in GB.51,52 Yet, local rewiring without compartment switching has been recognized as a mechanism for inactivating repression of proto-oncogenes in cancer.53,54These findings identify potentially targetable vulnerabilities with important therapeutic implications.
局限
Overexpression of HOXA10 has also been associated with worse prognosis and resistance to therapy in other cancer types such as prostate and gastric cancer.22 However, loss of HOXA10 is associated with progression in endometrial cancer.；However, in the high-HOX GS line LN-2683GS, the other HOX clusters showed higher activity (Figure 1, Figure S2A-C), reflecting intertumoral heterogeneity.Activation of the Canonical and Alternative HOXA10 Promoter in the High-HOX GS LineBased on our previous findings that attributed a special role of HOXA10 in the activation of the overall HOX signature in GB, we investigated the canonical and alternative HOXA10 promoters in LN-2540GS and LN-2669GS by ChIP-qPCR (Figure S8).；However, reduced cell proliferation and induction of a senescence-like phenotype are common stress responses.Investigating the HOXA cluster with multi-layered epigenomic profiling of high- and low-HOX GS lines revealed a permissive chromatin landscape in high-HOX lines with distinct CTCF loops and increased chromatin interactions within the extended HOXA region.
对本项目的价值
中高价值：属「衰老细胞清除 / SASP 轴」方向；细胞衰老 / senolytics / SASP栏目可用作本项目文献库与综述素材。 ｜ 价值分 3.0/5（★★★☆☆）
全文来源
PubMed PMC JATS（正文 46,145 字符，题名指纹 0.85，已过 PubMed PMCID 官方关联 + 题名指纹 + 正文长度归属校验）
原文题录
- 中文题名：BET 抑制协调 repression 胶质母细胞瘤干细胞相关 HOX 签名，揭示表观遗传脆弱性
- 英文标题：Bromodomain and extra-terminal motif (BET) inhibition induces coordinated repression of the stem cell-related HOX signature in glioblastoma uncovering an epigenetic vulnerability.
- 期刊与标识：Neuro-oncology advances · PMID 42974552 · DOI 10.1093/noajnl/vdag260 · PMC PMC13726806