Hasan Arif Ul, Sato Sachiko, Obara Mami, Kondo Yukiko, Taira Eiichi
Department of Pharmacology, School of Medicine, Iwate Medical University, Yahaba 028-3694, Japan.
Epigenomes. 2025 Jul 28;9(3):27. doi: 10.3390/epigenomes9030027.
Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Our findings establish the KYNU-HDAC6-complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches-such as HDAC6 and BET inhibition-represents a promising strategy to overcome complement-driven resistance in GBM therapy.
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，以其高度异质性和治疗抵抗性而闻名。补体信号失调和表观遗传改变与GBM进展有关。本研究确定了犬尿氨酸酶（KYNU），即犬尿氨酸途径中的一种关键酶，作为补体成分的新型调节因子，并在治疗靶点的背景下研究其与组蛋白脱乙酰酶6（HDAC6）的相互作用。使用公开可用的数据集（TCGA、GTEx、HPA）分析了GBM中KYNU的表达及其与补体信号的关联。通过LinkedOmics进行通路富集。在GBM细胞系（U87、U251、T98G）中进行的体外研究评估了KYNU沉默以及用HDAC6抑制剂（tubastatin）和BET抑制剂（阿哌巴酮）处理对基因表达和细胞活力的影响。生物信息学分析显示，与正常脑组织相比，GBM组织中KYNU显著过表达。KYNU表达与参与补体和凝血级联反应的基因呈正相关。体外实验表明，KYNU沉默降低了C3、C3AR1和C5AR1的表达，并抑制了GBM细胞活力。用tubastatin处理虽然降低了活力，但反常地上调了补体基因，提示治疗效果可能存在潜在局限性。然而，这种效应通过KYNU敲低得到缓解。阿哌巴酮和tubastatin联合处理有效地抑制了KYNU表达并增强了细胞毒性，特别是在补体高表达的细胞中。我们的研究结果确立了KYNU-HDAC6-补体轴为GBM中的关键调节途径。通过联合表观遗传方法（如HDAC6和BET抑制）靶向KYNU介导的补体激活是克服GBM治疗中补体驱动耐药性的一种有前景的策略。
