Great news, we have a new co-author publication out in the journal Oncogene! The work was lead by Professor Neil Watkins, and is titled “The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53”.
You can access the full article here [Link]
ABSTRACT: Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of- heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.
A defining feature in over 2/3rds of all solid tumours is the continual loss and gain of whole are small parts of chromosomes. This instability, or CIN for short, strongly implicated in tumour initiation, progression, chemoresistance and poor prognosis. CIN is created through failures during mitosis, whereby whole or parts of a chromosome are segregated incorrectly, thereby created daughter cells with unequal chromosome numbers. Consequently, understanding how mitosis is regulated is essential for uncovering the mechanisms allowing CIN to arise and drive cancer. In our recent publication, we discovered the mechanisms controlling the key regulatory pathway critical to ensuring cells exit mitosis correctly. At the centre of this pathway is a gene call MASTL (short for ‘Microtubule Associated Serine/Threonine Kinase-Like’). The primary function of MASTL is to ensure that the cellular breaks (the phosphatase PP2A), is turned off during mitosis so that the accelerator (Cdk1 kinase) can drive the cell into mitosis. Much like a car, having the accelerator and breaks on at the same time is a bad idea, unless you like the smell of burning rubber. To successfully exit mitosis, and to perfectly segregate chromosomes, the cell must take the foot off the accelerator and turn on the breaks. Because MASTL is the central regulator ensuring the breaks are coordinated with the accelerator, it is essential to understand how MASTL is controlled. To this end, we uncovered that MASTL must be rapidly turned off to allow cells to exit mitosis, and this inactivation is carried out by another cellular brake call PP1 phosphatase (Rogers et al, JCS 2016). Now that we have identified and mapped this novel mitotic exit switch, we hope to be able to shed new light on how CIN drives the initiation and evolution cancer. We believe that with further study we will be able to better predict patient response to chemotherapy, and also identify new ways to ‘switch off’ highly unstable tumours, thereby improving treatment for patients that currently have a very poor prognosis.
Image of Interphase HeLa cell stained for Actin (red), DNA (blue) and the co-localisation of MASTL and PP1 by Proximity Ligation Assay (PLA; green).
Credit: Sam Rogers and Cell Division Lab
There has been a bit of press lately suggesting that Antioxidants might actually be bad for cancer… not good as they are commonly promoted in the media.
IFLS has put together a great article on some of the reasons why antioxidants might not be such a great thing [Link].
In addition, we recently wrote a review article about how different ‘stresses’ including oxidation can affect mitosis, and cancer. We also came to a similar conclusion in our review, that antioxidants were a complicated and not always benifical for treating cancer. One of the main reason we suggested this was due to the fact that many common antioxidants are part of the Flavonoid family. On the surface that sound great, but many Flavonoids also happen to potently inhibit cyclin dependent kinases (Cdks). Coincidentally, our other recent article in Cell Cycle, showed that partial inhibition of Cdk1 can dramatically disrupt mitosis and drive severe cytokinesis defects and polyploidy (see video below). These mitotic defects are the foundation of chromosome instability (CIN), which is a hallmark of more aggressive cancer types, that are also resistant to most chemotherapies and treatments. In simple terms, there is a possibility that in some cases, taking large quantities of dietary Flavonoids (e.g red wine, dark chocolate etc) could drive the formation of more aggressive cancers. This is definitely an area that needs a lot more research, and as always make sure that you fully discuss any dietary and supplements with your oncologist.
This is what happens when a ‘fairly normal’ cancer cell is treated with low doses of a Cdk1 inhibitor.
Here is a picture of a polyploid cancer cell, which was produced by partially inhibiting Cdk1.