How HEXIM1 stops the spread of cancer - Part 2.

In the previous lab note we described how HEXIM1 turns off pro growth, proliferative and pro survival genes in cells by sequestering P-TEFb in a complex with 7SK snRNP. We termed this a P-TEFb 'dependent' mechanism.

There is another method however whereby HEXIM1 can turn off the expression of this subset of procancerous genes. Many genes have a region upstream called a response element (RE) which is used to recruit transcription factors (activator or repressor proteins which turn gene expression on or off). It turns out that HEXIM1 can bind these transcription factors and block them from recruiting P-TEFb for gene expression. Since the binding of HEXIM1 is to the transcription factors and not the P-TEFb we can think of this as a P-TEFb 'independent' mechanism.

But in reality, this is a synergistic regulatory process where high levels of HEXIM1 sequesters P-TEFb in an inactive 7SK snRNP complex, while other HEXIM1 molecules block the remaining 'free' P-TEFb from completing gene expression at RNA Pol II dependent genes. HEXIM1 is able to bind a whole slew of transcription factors, including many whose misregulation is commonly associated with the cancerous state. As such we can think of inducing high levels of HEXIM1 as equivalent to pushing the 'reset' button on a cancer cell. These less malignant cells are now much more amenable to surgical and radiation treatments.

Let's look at a very relevant example, Tamoxifen resistance in breast cancer.

 

Normally the hormone estrogen will recruit ER alpha (Estrogen Receptor alpha) to the ERE response element. Next P-TEFb will be recruited to express genes which are estrogen dependent via the RNA Pol II polymerase. However if there are high levels of HEXIM1 in the cell, the ER alpha transcription factor will be blocked in recruitment of P-TEFb by binding of HEXIM1.

Tamoxifen is an anti estrogen used to treat patients with ER alpha positive breast cancer (about 70% of initial diagnoses - see diagram below) and is an inhibitor of estrogen dependent gene expression. It turns out that this inhibitory effect of Tamoxifen requires HEXIM1 to happen and since patients are often maintained on Tamoxifen for up to 10 years to prevent recurrence of the cancer, over time Tamoxifen resistant cells can frequently arise. Tamoxifen resistance is very commonly seen after 5 or more years of Tamoxifen treatment because natural HEXIM1 levels drop, so we think that our inducing drugs can restore Tamoxifen sensitivity to breast cancer survivors - in addition to the other effects of HEXIM1 induction.

In our next lab note we'll look at the direct role of HEXIM1 in preventing metastasis - which is the key to making breast cancer a completely non lethal disease.