This research article investigates the mechanistic link between high iron levels and the development of colorectal cancers (CRCs), focusing on the reactivation of telomerase, an enzyme associated with cellular immortalization. The authors identify Pirin, an iron-sensing protein, as a crucial mediator that binds with oxidized iron (Fe3+) to reactivate the human telomerase reverse transcriptase (hTERT) subunit. This finding provides a molecular explanation for the known association between high dietary iron intake (such as red meat consumption) and increased CRC risk. Furthermore, the study pinpoints a small molecule, SP2509, which inhibits this process by competing with Fe3+ for binding to Pirin, suggesting a novel therapeutic approach for targeting telomerase-driven cancers, particularly those of the CMS3 subtype. The mechanism involves iron-activated Pirin stabilising the transcription factor Sp1 by repressing the E3 ubiquitin ligase FBXW7, which consequently drives hTERT expression.
Research paper:
Shanmugam R, Majee P, Shi W, Ozturk MB, Vaiyapuri TS, Idzham K, Raju A, Shin SH, Fidan K, Low JL, Chua JYH, Kong YC, Qi OY, Tan E, Chok AY, Seow-En I, Wee I, Macalinao DC, Chong DQ, Chang HY, Lee F, Leow WQ, Murata-Hori M, Xiaoqian Z, Shumei C, Tan CSH, Dasgupta R, Tan IB, Tergaonkar V. Iron (Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers. Cancer Discov. 2024 Oct 4;14(10):1940 1963.
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