Pillar 1 - FTO (new thread), page-1482

Hey mate. Welcome to the forum. Thank you for your kind words.

I haven't looked into our methylating cousins much, so you might be able to teach me a thing or two.

My understanding is there will are subsets of cancers that are driven by upregulated methylation (high methylators [METTL3/14/WTAP]: low demethylators [FTO/ALKBH5]) or demethylation (low methylators [METTL3/14/WTAP]: high demethylators [FTO/ALKBH5]). So, it's going to be common to find papers that determine an association between different cancers and either methylators or demethylator dysregulation.

Do you know whether FTO inhibition (induced by Bisantrene or any other FTO inhibitors you've come across) result in higher levels of WTAP/METTL3/METTL14 or does it simply reduce the proportion of demethylation to methylation (simply by a lower amount of FTO vs the methylases)?

Firstly, FTO inhibition induced by Zantrene does not alter the levels of FTO, rather Zantrene is occupying the catalytic pocket where a portion of the mRNA goes - this prevents the removal of the methyl group from the 6th carbon of Adenosine. I'm not aware of any research that has determined whether inhibition of FTO leads to upregulation of methylators, so I can't answer that. I have found it helpful thinking about methylation and demethylation as if it were on a sliding scale. If you had more demethylators than methylators, then the slide would move along the scale towards greater demethylation (which obviously alters the expression of genes and then proteins influencing cellular function), and vice versa if there were more methylators than demethylators. What the FTO inhibitor does is prevents the demethylation happening, so even though there are more demethylators than methylators, the slide would move along the scale towards greater methylation. An FTO inhibitor is going to be most useful when a cancer cell is utilizing that increased demethylation to drive tumorigenesis.

I guess I'm curious to understand how exactly Bisantrene/other FTO inhibitors could interact with cancers that don't just correlate to FTO expression (higher demethylase levels), but also exist/demonstrate higher levels of metastasis/aggression where methylases like WTAP/METTL3/METTL14 are low.

This is a great line of thought that I have also had and have discussed a very interesting paper addressing this in the following post. It starts to get very complex unpacking this because there is still so much we don't know. My understanding is that in high methylator cancer cells, the expression level of FTO within the cell is still regulating the expression of genes and proteins and influencing cellular function (albeit in a much less impactful way than the upregulated methylators driving tumorigenesis). Because the FTO level still controls genes and proteins, I believe that there is an opportunity for drug combinations to still take place. Obviously, cancer cells utilizing FTO to drive tumorigenesis will have the best response, but if the complete inhibition of FTO could downregulate key immune evasion, growth, or metabolism genes that provided some small benefit to another anti-cancer compound (anti-PD1, for example), then that would open the door for many more potential cancer patients irrespective of dynamic methylation/demethylation.

This is super complex and I hope I haven't lost you.