Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China.
Department of Hepatopancreatobiliary Surgery, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300060, China.
Aging (Albany NY). 2024 Oct 11;16(19):12850-12865. doi: 10.18632/aging.206108.
Ubiquitin-specific protease 4 (USP4) has been identified as a promising oncogenic factor implicated in various human malignancies. However, the exact biological functions and underlying mechanisms of USP4 in the progression of papillary thyroid carcinoma (PTC) remain elusive. In this study, we observed a marked upregulation of USP4 expression in PTC tumor tissues. Elevated levels of USP4 were significantly correlated with aggressive clinicopathological features and poor prognosis. Functional assays for loss-of-function demonstrated that silencing USP4 hindered the proliferation of PTC cells. Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells. Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways. In summary, our findings elucidate the critical involvement of the USP4/LDHA axis in driving PTC progression through the modulation of MAPK and AKT pathways, thereby identifying USP4 as a potential therapeutic target for the treatment of PTC.
泛素特异性蛋白酶 4（USP4）已被鉴定为一种有前途的致癌因子，与多种人类恶性肿瘤有关。然而，USP4 在甲状腺乳头状癌（PTC）进展中的确切生物学功能和潜在机制仍不清楚。在这项研究中，我们观察到 USP4 在 PTC 肿瘤组织中的表达明显上调。USP4 水平升高与侵袭性临床病理特征和不良预后显著相关。功能丧失的功能分析表明，沉默 USP4 可抑制 PTC 细胞的增殖。此外，我们的研究揭示了 USP4 与乳酸脱氢酶 A（LDHA）之间的特异性相互作用，其中 USP4 通过去泛素化在 PTC 细胞中发挥关键作用稳定 LDHA 蛋白水平。值得注意的是，这项研究表明，USP4 通过调节 MAPK 和 AKT 信号通路促进 PTC 增殖。综上所述，我们的研究结果阐明了 USP4/LDHA 轴通过调节 MAPK 和 AKT 通路在驱动 PTC 进展中的关键作用，从而确定 USP4 是治疗 PTC 的潜在治疗靶点。
