Do we finally know what MYC is doing in cancer?

Tens of thousands of papers have been written on what MYC might be doing in cancer.  I’ve been reading about Myc for years, and my notes on Myc  contain 60,000+ characters. Cancer cells must love MYC as around 70% of human cancers overexpress the MYC protein, which is a transcription factor turning on the expression of at least 1,500 genes.  Others say 2,000 ( 10% of all protein coding genes).  “Whatever the latest trend in cancer biology — cell cycle, cell growth, apoptosis, metabolism, cancer stem cells, microRNAs, angiogenesis, inflammation — Myc is there regulating most of the key genes”  [ Cell vol. 151 pp. 11 – 13 ’12 ].   An intriguing theory is that Myc is part of the Matthew syndrome — Matthew 25:29
“For everyone who has will be given more, and he will have an abundance.”  Translating this into molecular biological terms, Myc acts to amplify the transcriptional state of any gene which is actively being transcribed.

The old idea that cells just up and died when they got sick, is pretty much gone.  There are various types of cell death, each of which has an intricately programmed mechanism — apoptosis, ferroptosis, pyroptosis, and necroptosis.  The latter is common on cancer, particularly when attacked by the immune system. [ Proc. Natl. Acad. Sci. vol. 117 pp. 19982 – 19993 20 ] says that MYC acts as an antinecroptosis factor by inhibiting the interaction of RIPK1 and RIPK3 which goes on to trigger necroptosis. This may be why cancer cells so love MYC.  What is particularly fascinating (to neurologists at least) is that further along the path to necroptosis another protein (MLKL) forms cytoplasmic amyloid fibers as part of the process.  So here is a physiological use for amyloid (even though the net result is death).

Marshall McLuhan rides again

Marshall McLuhan famously said “the medium is the message”. Who knew he was talking about molecular biology?  But he was, if you think of the process of transcription of DNA into various forms of RNA as the medium and the products of transcription as the message.  That’s exactly what this paper [ Cell vol. 171 pp. 103 – 119 ’17 ] says.

T cells are a type of immune cell formed in the thymus.  One of the important transcription factors which turns on expression of the genes which make a T cell a Tell is called Bcl11b.  Early in T cell development it is sequestered away near the nuclear membrane in highly compacted DNA. Remember that you must compress your 1 meter of DNA down by 100,000fold to have it fit in the nucleus which is 1/100,000th of a meter (10 microns).

What turns it on?  Transcription of nonCoding (for protein) RNA calledThymoD.  From my reading of the paper, ThymoD doesn’t do anything, but just the act of opening up compacted DNA near the nuclear membrane produced by transcribing ThymoD is enough to cause this part of the genome to move into the center of the nucleus where the gene for Bcl11b can be transcribed into RNA.

There’s a lot more to the paper,  but that’s the message if you will.  It’s the act of transcription rather than what is being transcribed which is important.

Here’s more about McLuhan — https://en.wikipedia.org/wiki/Marshall_McLuhan

If some of the terms used here are unfamiliar — look at the following post and follow the links as far as you need to.  https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/

Well that was an old post.  Here’s another example [ Cell vol. 173 pp. 1318 – 1319, 1398 – 1412 ’18 ] It concerns a gene called PVT1 (Plasmacytoma Variant Translocation 1) found 25 years ago.  It was the first gene coding for a long nonCoding (for proteins RNA (lncRNA) found as a recurrent breakpoint in Burkitt’s lymphoma, which sadly took a friend (Nick Cozzarelli) far too young as (he edited PNAS for 10 years).

So PVT1 is involved in cancer.  The translocation turns on expression of the myc oncogene, something that has been studied out the gazoo and we’re still not sure of how it causes cancer. I’ve got 60,000 characters of notes on the damn thing, but as someone said 6 years ago “Whatever the latest trend in cancer biology — cell cycle, cell growth, apoptosis, metabolism, cancer stem cells, microRNAs, angiogenesis, inflammation — Myc is there regulating most of the key genes”

We do know that the lncRNA coded by PVT1 in some way stabilizes the myc protein [ Nature vol. 512 pp. 82 – 87 ’14 ].  However the cell experiments knocked out the lncRNA of PVT1 and myc expression was still turned on.

PVT1 resides 53 kiloBases away from myc on chromosome #8.  That’s about 17% of the diameter of the average nucleus (10 microns) if the DNA is stretched out into the B-DNA form seen in all the textbooks.  Since each base is 3.3 Angstroms thick that’s 175,000 Angstroms 17,500 nanoMeters 1.7 microns.  You can get an idea of how compacted DNA is in the nucleus when you realize that there are 3,200,000,000/53,000 = 60,000 such segments in the genome all packed into a sphere 10 microns in diameter.

To cut to the chase, within the PVT1 gene there are at least 4 enhancers (use the link above to find what all the terms to be used actually mean).  Briefly enhancers are what promoters bind to to help turn on the transcription of the genes in DNA into RNA (messenger and otherwise).  This means that the promoter of PVT1 binds one or more of the enhancers, preventing the promoter of the myc oncogene from binding.

Just how they know that there are 4 enhancers in PVT1 is a story in itself.  They cut various parts of the PVT1 gene (which itself has 306,721 basepairs) out, and place it in front of a reporter gene and see if transcription increases.

The actual repressor of myc is the promoter of PVT1 according to the paper (it binds to the enhancers present in the gene body preventing the myc promoter from doing so).  Things may be a bit more complicated as the PVT1 gene also codes for a cluster of 7 microRNAs and what they do isn’t explained in the paper.

So it’s as if the sardonic sense of humor of ‘nature’, ‘evolution’, ‘God’, (call it what you will) has set molecular biologists off on a wild goose chase, looking at the structure of the gene product (the lncRNA) to determine the function of the gene, when actually it’s the promoter in front of the gene and the enhancers within which are performing the function.

The mechanism may be more widespread, as 4/36 lncRNA promoters silenced by CRISPR techniques subsequently activated genes in a 1 megaBase window (possibly by the same mechanism as PVT1 and myc).

Where does McLuhan come in?  The cell paper also notes that lncRNA gene promoters are more evolutionarily conserved than their gene bodies.  So it’s the medium (promoter, enhancer) is the message once again (rather than what we thought the message was).