Gao Jiaming, Liu Qian, Xu Ying, Gong Xin, Zhang Runyun, Zhou Chenglin, Su Zhaoliang, Jin Jianhua, Shi Haifeng, Shi Juanjuan, Hou Yongzhong
Department of Oncology, The Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, Jiangsu Province, China.
Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China.
Oncotarget. 2015 Dec 29;6(42):44635-42. doi: 10.18632/oncotarget.5988.
PPARα belongs to the peroxisome-proliferator-activated receptors (PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis, while the molecular mechanism is still unclear. Here we report that PPARα serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPARα physically bound to Bcl2 protein. In this process, PPARα/C102 was critical for PPARα binding to BH3 domain of Bcl2, subsequently, PPARα transferred K48-linked polyubiquitin to lysine-22 site of Bcl2 resulting in its ubiquitination and proteasome-dependent degradation. Importantly, overexpression of PPARα enhanced cancer cell chemotherapy sensitivity. In contrast, silenced PPARα decreased this event. These findings revealed a novel mechanism of PPARα governed endogenous Bcl2 protein stability leading to reduced cancer cell chemoresistance, which provides a potential drug target for cancer treatment.
过氧化物酶体增殖物激活受体α（PPARα）属于过氧化物酶体增殖物激活受体（PPARs）家族，其在抑制细胞增殖和肿瘤发生中起关键作用，但其分子机制仍不清楚。在此我们报告，PPARα作为一种E3泛素连接酶来调控Bcl2蛋白的稳定性。PPARα与Bcl2蛋白发生物理结合。在此过程中，PPARα/C102对于PPARα与Bcl2的BH3结构域结合至关重要，随后，PPARα将K48连接的多聚泛素转移至Bcl2的赖氨酸-22位点，导致其泛素化及蛋白酶体依赖性降解。重要的是，PPARα的过表达增强了癌细胞的化疗敏感性。相反，PPARα沉默则降低了这一效应。这些发现揭示了PPARα调控内源性Bcl2蛋白稳定性从而降低癌细胞化疗耐药性的新机制，这为癌症治疗提供了一个潜在的药物靶点。
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