Pathania Anup S, Murugan Anjana, Zahid Areem, Chava Haritha, Coulter Don W, Calin George A, Challagundla Kishore B
The Child Health Research Institute, Department of Biochemistry and Molecular Biology, and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
UNMC High School Alliance, Department of Biochemistry and Molecular Biology, and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Mol Ther Oncol. 2024 Dec 6;33(1):200916. doi: 10.1016/j.omton.2024.200916. eCollection 2025 Mar 20.
Neuroblastoma (NB), a devastating pediatric cancer originating from neural crest cells crucial for nervous system development, poses a significant therapeutic challenge. Despite chemotherapy being the primary treatment, approximately 70% of high-risk NB cases develop resistance. Autophagy is vital for neuronal development, balance, and differentiation of neural stem cells into mature neurons. However, the intricate mechanisms governing autophagy and the pivotal genes orchestrating its regulation in NB remain largely elusive. In this study, we first identified Sin3A Associated Protein 30 (SAP30) as a novel regulator of autophagy in NB. Silencing SAP30 inhibits autophagy and disrupts starvation-induced physiological autophagy in NB cells. Conversely, ectopic expression of SAP30 induces autophagy in NB cells under normal or starvation conditions. Mechanistically, SAP30 transcriptionally regulates STX17, a crucial protein involved in autophagosome-lysosome fusion during autophagy. Reduction of SAP30 decreases STX17 expression, hindering its translocation to the autophagic membrane and inhibiting autophagosome-lysosome fusion. SAP30-mediated autophagy enhances cell growth and provides protection in NB cells treated with chemotherapy drugs. Notably, suppressing SAP30 increases LC3B accumulation, an autophagy marker, along with reduced proliferation markers, both and in PDX tumors. Therefore, SAP30 emerges as a potential target to enhance NB responsiveness to chemotherapy drugs.
神经母细胞瘤（NB）是一种源自对神经系统发育至关重要的神经嵴细胞的毁灭性儿科癌症，带来了重大的治疗挑战。尽管化疗是主要治疗方法，但约70%的高危NB病例会产生耐药性。自噬对于神经元发育、神经干细胞的平衡以及分化为成熟神经元至关重要。然而，在NB中，控制自噬的复杂机制以及协调其调控的关键基因在很大程度上仍不清楚。在本研究中，我们首先确定Sin3A相关蛋白30（SAP30）是NB中自噬的一种新型调节因子。沉默SAP30可抑制自噬，并破坏NB细胞中饥饿诱导的生理性自噬。相反，在正常或饥饿条件下，SAP30的异位表达可诱导NB细胞中的自噬。从机制上讲，SAP30转录调控STX17，STX17是自噬过程中参与自噬体-溶酶体融合的关键蛋白。SAP30的减少会降低STX17的表达，阻碍其向自噬膜的转运，并抑制自噬体-溶酶体融合。SAP30介导的自噬增强细胞生长，并在用化疗药物处理的NB细胞中提供保护。值得注意的是，抑制SAP30会增加自噬标志物LC3B的积累，同时降低增殖标志物，在PDX肿瘤中也是如此。因此，SAP30成为增强NB对化疗药物反应性的潜在靶点。
