Research Paper Volume 13, Issue 4 pp 5034—5054
Transcriptional dysregulation of TRIM29 promotes colorectal cancer carcinogenesis via pyruvate kinase-mediated glucose metabolism
- 1 Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang 050000, Hebei, P.R. China
- 2 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
- 3 Department of Thoracic Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang 050000, Hebei, P.R. China
- 4 Department of General Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang 050000, Hebei, P.R. China
- 5 Department of General Surgery, The 3rd Affiliated Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, P.R. China
Received: May 26, 2020 Accepted: September 28, 2020 Published: January 20, 2021https://doi.org/10.18632/aging.202414
How to Cite
Copyright: © 2021 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 in vitro and in vivo. 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.