FTO‑IT1 as a Promising Candidate Biomarker For Prostate Cancer

Androgen Deprivation Therapy is the sure fire way to treat prostate cancer. The patients are deprived of androgens by inhibiting their synthesis or through competitive inhibion of receptors using inhibitors, as the cancer progression predominantly depends on the androgen receptor signalling. When the cancer becomes castration resistant the second line of treatment involves enzalutamide and doxetacel however, the patients still progress on treatment with this therapy.

Post transcriptional modifications are of RNA is vital for cell survival and out of this m6A is the most common in vertebrates. the reader RBM 15 and its paralouge RBM 15B  and the writer complex METL3 is responsible for catalyzing the m6A modification. The modification however is reversible by demethylation using FTO and AlkB homolog 5 but the mechanism of regulation of the writer complex remains unknown. 

FTO-IT1 (Fat mass and Obesity-associated intronic transcript 1) is a long ncRNA (non-coding RNA) transcribed from intron 8 of FTO gene. It was found that the FTO-IT1 was overexpressed in cell lines resisitant to enzalutamide and upon comparing the control vs resistant cell lines the FTO-IT1 expression was higher in the resistant cell lines and meta- analysis of prostate cancer smaples showed that patients in advanced stages also had higher expression FTO-IT1. the knocking out of the FTO-IT1 gene resensitised the cells to enzalutamide in the resistant cell lines. 

Figure:FTO-IT1 in regulating mRNA m6A methylation

P53 transcriptional target genes was shown to be hyper regulated by depletion of FTO-IT1. P53 signaling is known to be activated in response to DNA damage and it regulates however, only a subset of P53 targeted genes are affected by m6A modificationgenes related to cell cycle and apoptosis. Overexpressed FTO-IT1 could be a viable biomarker and therapeutic target of tumors, but the study has only been conducted in vivo models. Further validation trials are needed to show proof of concept in humans.

REFERENCE:

Zhang, J., Wei, J., Sun, R., Sheng, H., Yin, K., Pan, Y., Jimenez, R., Chen, S., Cui, X. L., Zou, Z., Yue, Z., Emch, M. J., Hawse, J. R., Wang, L., He, H. H., Xia, S., Han, B., He, C., & Huang, H. (2023). A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling. Molecular cell, 83(15), 2692–2708.e7. https://doi.org/10.1016/j.molcel.2023.06.024

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