What to do about EZH2 hyperactivity in myeloma…?

I read a 2005 “Oncogene” study (full text available for free: http://tinyurl.com/3y4fclq) for one, and only one!, reason, which we will get to in a second. Let’s see…I could simply write that, according to this study, EZH2, which stands for “enhancer of zeste homolog 2″ (ah, don’t ask!), is a pesky Polycomb repressor gene that is hyperactive, in a bad sense!, in myeloma as well as other types of cancer…but no, that is not enough. We must examine a few excerpts that will help us understand the connection with the second study discussed in this post…

The “Oncogene” study tells us that Normal bone marrow plasma cells do not express ezh2; however, gene expression is induced and correlates with tumor burden during progression of this disease. What this means is that EZH2 is present only in myeloma plasma cells, not in normal plasma cells. Furthermore, the hyperactivity of EZH2 increases as myeloma progresses (a bad thing, clearly): that is basically what “correlates with tumor burden” means.

These researchers discovered that EZH2 is closely linked to IL-6, which is perhaps the most written-about myeloma interleukin (I have written a lot about it, too). Just as a reminder: IL-6 is involved in a host of myeloma-centered activities, including progression and proliferation… If you would like to read more about the link between the Polyhooligan and IL-6, please have a look at the above-mentioned study…

Let’s get back to the point, now. When the EZH2 Polyhooligan becomes overly active and hopped up (=overexpressed), myeloma cells are as happy as clams and grow like mad; the reverse occurs, however, when this Polyhooligan is inhibited…that is, myeloma cells stop growing when EZH2 is inhibited. This is a very VERY important point. Uhm, okay, I won’t go into the part about “mutant N- or K-ras gene,” except to say that EZH2 is involved in that process, too. EZH2 is a very bad, BAD boy!

The study tells us that this super-active Polyhooligan is very much involved in metastatic prostate cancer and aggressive breast cancer. But it adds a titbit that is important for us myeloma folks to know: ezh2 was found to be one of the 30 genes that could distinguish between normal PC and MGUS (MM1) and aggressive myeloma (MM4). Eh…

As mentioned above, sorry for the repetition!, this particular Polyhooligan can be found only in multiple myeloma cells, not in normal bone marrow plasma cells. And EHZ2 is also much more active and wild in Stage 4 than in Stage 1. Its activity is therefore associated with myeloma progression.

Well, the researchers discovered that the growth of myeloma cells was significantly affected when EZH2 was blocked (they used a specific synthetic EZH2-inhibitor known as siRNA). They conclude: This study also suggests that EZH2 is required for MM cell growth since all MM cell lines studied were significantly growth inhibited upon EZH2 siRNA treatment. Wow, this sentence is of immense importance…

I could go on and on and on, but I don’t want to beat my point to death, especially since you can read the full study online for free. All we really need to keep in mind is that this particular Polyhooligan is linked to myeloma cell proliferation and must be stopped. But how?

I am sure that by now most of you have already guessed that our best buddy, curcumin, inhibits EZH2. Ah yes. Now, even though the amazing anti-this-and-that-and-everything properties of curcumin shouldn’t surprise me anymore (after all, I have spent the past four years researching this topic!), I have to admit that I was indeed surprised to find this July 2010 study on the extraordinary effects of curcumin on EZH2 and metastatic breast cancer cells: http://tinyurl.com/3y5plyq Before I forget, I would like to thank a blog reader/friend (thanks!) for sending me the full text…

The basic information is in the abstract: curcumin inhibits EZH2 in a highly metastatic breast cancer cell line. Please pay attention to the underlined (by moi!) items mentioned in this sentence: “Further investigation revealed that curcumin-induced down-regulation of EZH2 through stimulation of three major members of the mitogen-activated protein kinase (MAPK) pathway: c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase.”

These three kinases (=a kinase is merely a type of protein, by the way) are important in myeloma, too. Quelle surprise…not. For more information, please have a look at this study: http://tinyurl.com/35rokpa (hmmm, at some point I should probably devote a post to galectins, which I’d never heard of before…).

Let’s dive right into the breast cancer-curcumin-EZH2 study. It almost immediately refers to the 2004 study (see my July 26 post on curcumin and MEL18), which suggests that curcumin might be involved in the regulation of PcG proteins and related signalling pathways

Further on we read: It is known that the enhancer of zeste homolog 2 (EZH2) is a critical component of PcG proteins, and that EZH2 plays an important role in cell proliferation and cell cycle regulation. The overexpression of EZH2 has also been reported to be linked to invasive growth, aggressive clinical behavior and poor prognoses of breast cancers.

These researchers discovered that curcumin inhibited the proliferation of a particularly aggressive breast cancer line in a dose- and time-dependent manner. This inhibition was significant when compared to untreated control cells, and the dose used was a non-toxic one. (For those with a scientific inclination: cell development was arrested in the G1 phase.)

The Discussion part contains a lot of food for thought and is not too difficult to follow (in fact, it is also a bit repetitive…): Recently, polycomb group proteins have been suggested as candidates for molecular targets of breast cancer treatment; and a critical component of the polycomb group proteins is EZH2. It has been found that EZH2 expression is significantly up-regulated in invasive breast carcinoma and cancer metastases, and that overexpression of EZH2 is associated with poor outcomes in breast cancer patients.

The researchers observed that the activity of EZH2 decreased as soon as curcumin managed to block the proliferation of these breast cancer cells. They therefore surmised that these two events might be connected–curcumin stops the proliferation of the breast cancer cell line, at least in part, by the down-regulation of EZH2 expression and its activity.

The researchers also mention a recent study showing that curcumin can activate MAPK signaling pathways to induce cell apoptosis in HCT116 cells and cisplatin-resistant human ovarian cancer cells. I have a good reason for mentioning this part: the activation of this particular pathway plays an important role in the annihilation of myeloma cells, too (a number of studies on PubMed confirm this point, including the above-mentioned galectin study).

When the MAPK pathway was inhibited, so was the curcumin-induced down-regulation of EZH2 expression, the researchers found. Therefore, the activation of MAPK seems to help curcumin to have an impact on the activity of EZH2. Sounds like gibberish, I know. But, in a nutshell, curcumin activates the MAPK signalling pathway AND decreases the hyperactivity of EZH2 in metastatic breast cancer cells, thus inhibiting their proliferation…wowiezeeewee!

The researchers conclude that curcumin, known to be pharmacologically safe, could profitably be used to target EZH2 for breast cancer treatment.

Indeed…not just for breast cancer, it would seem…based on my own findings…okay, I need a nap, now!


Leave a Reply

Your email address will not be published. Required fields are marked *