Prostate Cancer: New insights from lncRNA world

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Uncontrolled expression of IncRNAs induces invasive cancer growth. Image by Dheepa Balasubramanian, PhD, all rights reserved

Why is it that doctors and scientists struggle day in and day out to treat and find cures for cancer, and yet the number of drugs and diagnostic markers that are actually successful in the clinical setting are but a few?

It is a well established, albeit, frustrating fact that cancer is a heterogeneous and complex disease.

We can compare cancer to a huge jigsaw puzzle that doctors and scientists are just beginning to solve, by finding and fitting in the multitude of pieces, in order to understand all the pathways involved, and how cancer cells outsmart the immune system.

Androgen Receptor-mediated Gene Expression in Prostate Cancer

Prostate cancer is an aggressive tumor that is dependent on an androgen receptor for its growth, proliferation and survival. Upon binding of androgen, the hormone, the androgen receptor (AR) kicks off a cascade of events leading to activation of its target genes.

So, it makes perfect sense to starve the cancer cells of androgen, as a first line of treatment for prostate cancer. Unfortunately, the disease does recur in 2-3 years, and in some cases, continues to grow even in the absence of the hormone (androgen-resistant, ARPCa). The assumption being that mutations in AR make it possible for AR to activate gene expression in an uncontrolled manner, in order to trigger the inhibition of apoptosis and proliferation of cancer cells.

Prostate Cancer’s Abnormal Expression of lncRNAs

The latest discovery by Yang and colleagues have shown that a class of regulatory RNAs, long non-coding RNAs (lncRNA), specifically PRNCR1 and PCGEM1, empowers the cancer cells through AR signaling pathways to become highly invasive and treatment-resistant. Long non-coding RNAs are longer than 200 nt, and do not code for proteins, but perform vital regulatory roles in chromatin remodeling, transcription, splicing, RNA decay, enhancer function, and epigenetic regulation.

Abnormal regulation of lncRNAs in cancer can alter gene expression in several ways: inhibit transcription factor activity, prevent RNA polymerase II binding, or recruit common epigenetic modifiers like chromatin modifying complexes, that can then subsequently alter the expression of a larger subset of target genes of importance.

lncRNAs: PCGEM1 and PRNCR1: How They Work

Through cleverly designed experiments, the authors revealed that the association of PRNCR1 at C-terminal portion of AR, bound at enhancers, is necessary for binding of the second lncRNA, PCGEM1 to N-terminus of AR.

For this interaction, AR must be active and methylated by DOTL1 protein.

PCGEM1 subsequently recruits another protein pygopus2 (Pygo2) that acts as a mediator between the enhancer and promoter region of AR target genes, through the histone mark, H3K4me31,2.

Of course, the best experiment to document the unequivocal role of these lncRNAs in androgen-dependent and androgen–independent activation of AR target genes in prostate cancer cells is to knockdown the lncRNAs and examine its effects on the tumor.

Remarkably, the suppression of the two lncRNAs inhibited AR target gene expression and tumor growth in cancer cells and animal models as well.

IncRNA Study: What’s the Big Deal?

The reason this study is important, is because in a small percentage of prostate cancers, the AR lacks the C-terminus, and is found locked in a “constitutively ON” mode.

The N-terminal half of the AR protein, as illustrated in this study, is bound by PCGEM1 that can function to turn on its targets, even in the absence of the other half of the AR protein.

In this study, the authors demonstrated the ever-increasing presence of long non-coding RNAs in the pathogenesis of cancer. This is possibly one vital piece that fits in perfectly in the puzzle, but we have a long way to go.

Resources

Yang L, et all. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. (2013). Nature: International Weekly Journal of Science. Accessed by September 2, 2013.

Schmitt A.M, Chang H.Y. Gene regulation: Long RNAs wire up cancer growth. (2013). Nature: International Weekly Journal of Science. Accessed by September 2, 2013.

Balk S.P, Knudsen K.E. AR, the cell cycle, and prostate cancer. (2008). Nuclear Receptor Signaling. Accessed September 2, 2013.

Niland C.N., Merry C.R., Khalil A.M. Emerging roles for long non-coding RNAs in cancer and neurological disorders. (2012). Frontiers in Genetics.  Accessed September 2, 2013.

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