Jing Doudou, Wu Wei, Huang Xin, Zhang Zhenhao, Chen Xuanzuo, Huang Fuhua, Liu Jianxiang, Zhang Zhicai, Shao Zengwu, Pu Feifei
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
FEBS J. 2025 Apr;292(7):1798-1812. doi: 10.1111/febs.17375. Epub 2025 Jan 23.
Osteosarcoma, a malignant bone tumor that occurs in adolescents, proliferates and is prone to pulmonary metastasis. Osteosarcoma is characterized by high genotypic heterogeneity, making it difficult to identify reliable anti-osteosarcoma targets. The genotype of osteosarcoma may be highly dynamic, but its high dependence on energy remains constant. Fortunately, tumors tend to have relatively consistent metabolic types. Targeting metabolism with anti-tumor therapies is a new strategy for treating tumors. Genes related to carbohydrate metabolism are widely and highly expressed in tumor tissues. Transketolase (TKT), a key enzyme at the non-oxidative stage of the pentose phosphate pathway, is up-regulated in various tumors. In the present study, TKT promoted osteosarcoma cell proliferation non-metabolically. Specifically, TKT bound directly to amino acid residues of Yin Yang 1 (YY1) at amino acids 201-228, stimulating YY1 to bind to the promoter of P21 activated kinase 4 (PAK4) and resulting in PAK4 expression and activation of the phosphoinositide 3-kinase-Akt signaling pathway. Additionally, we designed a peptide, YY1-PEP, based on the exact mechanism of how TKT promotes osteosarcoma. Per in vivo and in vitro experiments, YY1-PEP displayed anti-osteosarcoma properties. The present study provides a new feasible strategy against osteosarcoma progression.
骨肉瘤是一种发生于青少年的恶性骨肿瘤，具有增殖性且易于发生肺转移。骨肉瘤的特点是基因型高度异质性，这使得难以确定可靠的抗骨肉瘤靶点。骨肉瘤的基因型可能高度动态变化，但其对能量的高度依赖性保持不变。幸运的是，肿瘤往往具有相对一致的代谢类型。用抗肿瘤疗法靶向代谢是一种治疗肿瘤的新策略。与碳水化合物代谢相关的基因在肿瘤组织中广泛且高度表达。转酮醇酶（TKT）是磷酸戊糖途径非氧化阶段的关键酶，在各种肿瘤中上调。在本研究中，TKT以非代谢方式促进骨肉瘤细胞增殖。具体而言，TKT直接与阴阳1（YY1）的201 - 228位氨基酸残基结合，刺激YY1与p21激活激酶4（PAK4）的启动子结合，导致PAK4表达并激活磷酸肌醇3激酶 - 蛋白激酶B信号通路。此外，我们基于TKT促进骨肉瘤的确切机制设计了一种肽YY1 - PEP。通过体内和体外实验，YY1 - PEP显示出抗骨肉瘤特性。本研究为对抗骨肉瘤进展提供了一种新的可行策略。
