Song Xinyi, Rao Haipeng, Huang Chunchun, Huang Miaoling, Ma Ying, Xin Jingyu, Hou Jiajia, Hu Zhigang, He Lingfeng, Pan Feiyan, Yang Lingdong, Guo Zhigang
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing 210023, China.
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing 210023, China.
Int J Biol Macromol. 2025 Jun;311(Pt 3):143885. doi: 10.1016/j.ijbiomac.2025.143885. Epub 2025 May 1.
Fumarate hydratase (FH) catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle. Its deficiency leads to fumarate accumulation, which is associated with kidney cancer metastasis, though the exact mechanisms remain unclear. Here, we identify prolyl 4-hydroxylase beta (P4HB) as a novel fumarate target in FH-deficient cancer cells that promotes migration and invasion. FH knockdown in human renal cancer cells significantly enhanced migratory and invasive capacities by 10- and 8-fold, respectively. Mechanistically, fumarate-induced succination stabilizes P4HB, promoting type I collagen production and enhancing tumor metastasis. P4HB knockdown markedly suppresses FH deficiency-induced metastasis in xenograft models. Fluorescence intensity in the FH knockdown group was about 10-fold higher, and tumor-bearing liver weight was approximately 1.5-fold greater than that in the FH and P4HB co-knockdown group. These results underscore the pivotal role of P4HB in metastasis. Additionally, we reveal NDP52 as a specific autophagy receptor that recognizes and binds to P4HB, mediating its degradation through the autophagy-lysosome pathway. However, succination of P4HB disrupts this recognition, interaction, and degradation, stabilizing P4HB. Together, these findings provide new insights into how fumarate-mediated succination affects P4HB protein stability and cancer metastasis, and suggest that P4HB could serve as a potential therapeutic target in FH-deficient cancers.
延胡索酸水合酶（FH）在三羧酸循环中催化延胡索酸转化为苹果酸。其缺乏会导致延胡索酸积累，这与肾癌转移有关，但其确切机制仍不清楚。在此，我们确定脯氨酰4-羟化酶β（P4HB）是FH缺陷癌细胞中的一种新型延胡索酸靶点，可促进细胞迁移和侵袭。在人肾癌细胞中敲低FH分别显著增强了其迁移和侵袭能力10倍和8倍。从机制上讲，延胡索酸诱导的琥珀酰化使P4HB稳定，促进I型胶原蛋白的产生并增强肿瘤转移。在异种移植模型中，敲低P4HB可显著抑制FH缺乏诱导的转移。FH敲低组的荧光强度约高10倍，荷瘤肝脏重量比FH和P4HB共同敲低组大约1.5倍。这些结果强调了P4HB在转移中的关键作用。此外，我们揭示NDP52是一种特异性自噬受体，可识别并结合P4HB，通过自噬-溶酶体途径介导其降解。然而，P4HB的琥珀酰化会破坏这种识别、相互作用和降解，从而使P4HB稳定。总之，这些发现为延胡索酸介导的琥珀酰化如何影响P4HB蛋白稳定性和癌症转移提供了新的见解，并表明P4HB可能作为FH缺陷型癌症的潜在治疗靶点。
