Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang 050000, Hebei, P.R. China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
Aging (Albany NY). 2021 Jan 20;13(4):5034-5054. doi: 10.18632/aging.202414.
Targeted molecular therapy is the most effective treatment for cancer. An effective therapeutic target for colorectal cancer (CRC) is urgently needed. However, the mechanisms of CRC remain poorly understood, which has hampered research and development of CRC-targeted therapy. TRIM29 is a ubiquitin E3 ligase that has been reported as an oncogene in several human tumors. In this study, we show that increased levels of TRIM29 were detected in CRC compared with normal tissues and were associated with poor clinical outcome, advanced stage and lymph node metastasis, particularly those with right-sided colorectal cancer (RSCC). Notably, GATA2 (GATA Binding Protein 2) transcriptionally repressed TRIM29 expression. The loss of GATA2 and high expression of TRIM29 occur more frequently in RSCC than in left-sided colorectal cancer (LSCC). Functional assays revealed that TRIM29 promotes the malignant CRC phenotype and . Mechanistic analyses indicate that TRIM29 promotes pyruvate kinase (mainly PKM1) degradation via the ubiquitin-proteasome pathway. TRIM29 directly targets PKM1 to reduce PKM1/PKM2 ratio, which results in PKM2-mediated aerobic glycolysis (Warburg effect) acting as the dominant energy source in CRC. Our findings suggest that TRIM29 acts as a tumor promoter in CRC, especially in RSCC, and is a potential therapeutic target for CRC treatment.
靶向分子治疗是癌症最有效的治疗方法。迫切需要找到治疗结直肠癌（CRC）的有效治疗靶点。然而，CRC 的发病机制仍不清楚，这阻碍了 CRC 靶向治疗的研究和开发。TRIM29 是一种泛素 E3 连接酶，已在几种人类肿瘤中被报道为致癌基因。在本研究中，我们发现与正常组织相比，CRC 中 TRIM29 的水平升高，并且与不良临床结局、晚期和淋巴结转移相关，尤其是右侧结直肠癌（RSCC）。值得注意的是，GATA2（GATA 结合蛋白 2）转录抑制 TRIM29 的表达。与 LSCC 相比，RSCC 中更频繁地发生 GATA2 的缺失和 TRIM29 的高表达。功能分析表明，TRIM29 通过泛素蛋白酶体途径促进恶性 CRC 表型。机制分析表明，TRIM29 通过泛素蛋白酶体途径促进丙酮酸激酶（主要是 PKM1）降解。TRIM29 直接靶向 PKM1 以降低 PKM1/PKM2 比值，导致 PKM2 介导的有氧糖酵解（Warburg 效应）作为 CRC 中的主要能量来源。我们的研究结果表明，TRIM29 在 CRC 中作为肿瘤促进剂起作用，尤其是在 RSCC 中，是 CRC 治疗的潜在治疗靶点。
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