Maite Huarte ^{1, 2}, and  John L. Rinn ^{1, 2},*

¹ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
² Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

*To whom correspondence should be addressed.
Tel: +1 6177352550;    Fax: +1 6177352480;    Email: jrinn@broadinstitute.org

Received July 17, 2010.   Revision received August 6, 2010.   Accepted August 16, 2010.

Cellular homeostasis is achieved by the proper balance of regulatory networks that if disrupted can lead to cellular transformation. These cell circuits are fine-tuned and maintained by the coordinated function of proteins and non-coding RNAs (ncRNAs). In addition to the well-characterized protein coding and microRNAs constituents, large ncRNAs are also emerging as important regulatory molecules in tumor-suppressor and oncogenic pathways. Recent studies have revealed mechanistic insight of large ncRNAs regulating key cancer pathways at a transcriptional, post-transcriptional and epigenetic level. Here we synthesize these latest advances within the context of their mechanistic roles in regulating and maintaining cellular equilibrium. We posit that similar to protein-coding genes, large ncRNAs are a newly emerging class of oncogenic and tumor-suppressor genes. Our growing knowledge of the role of large ncRNAs in cellular transformation is pointing towards their potential use as biomarkers and targets for novel therapeutic approaches in the future.

The ultimate cause of cancer is the alteration of the balanced
harmony of cellular networks and gene expression programs
that maintain cellular homeostasis. Even the slightest perturbation
of these pathways can result in cellular transformation.
For decades, genetic studies have revealed the mutational
alteration of genes that control these critical pathways such
as DNA damage response, growth arrest, cell survival or the
apoptotic pathway (1).

Genes controlling such balance can be classified into two
major groups: tumor-suppressor genes and oncogenes. Tumorsuppressor
genes protect cells against deleterious mutations
and cellular regulation that could prime transformation. Conversely,
genes that initiate the cellular transformation
process upon inappropriate activation comprise oncogenes.
Recent research points to the need for an expanded definition
beyond just protein-coding genes to also include ‘tumorsuppressor
non-coding RNAs (ncRNAs)’ and ‘oncogenic ncRNAs’.

Indeed, numerous profiling and characterization studies of
microRNAs have identified critical roles for ncRNAs in
cancer (2–5). MicroRNA alterations have been involved in
the initiation and progression of human cancer. Furthermore,
microRNA-expression profiling of human tumors has identified
signatures associated with diagnosis, staging, progression,
prognosis and response to treatment (4, 6–12). Given that
microRNAs primarily function as post-transcriptional regulators
(13), they can act as tumor suppressor or oncogenes
depending on their target genes (14). But in addition to the
relatively well-described microRNAs, the growing knowledge
of the mammalian non-coding transcriptome is revealing that
the genome is also replete with large ncRNAs, which could
have a major role in the development and progression of
cancer, although their mechanisms of function remain less
well understood (15–19).

Besides genetic mutations of tumor suppressor or oncogenes,
a great deal of evidence indicates that epigenetic alteration
is also a major factor contributing to tumor transformation
and cancer (20). Intriguingly, a number of studies suggest that
large non-coding RNAs are key components of the epigenetic
regulatory networks.

For example, it is now well established that some large
ncRNAs such as XIST, HOTAIR, AIR and KCNQ1OT1 interact
with chromatin-remodeling complexes targeting them to
specific genes to exert their functions (16, 21–25). It has
been proposed that different ncRNAs may serve as molecular
scaffolds for those complexes so they can function in an
appropriate spatial and temporal manner (26–28). In support
of this hypothesis, a recent study shows that as many as
20% of large intergenic ncRNAs (lincRNAs) expressed in a
given cell associate with chromatin-repressive complexes
such as polycomb repressive complex 2 (PRC2) and that many
of these lincRNAs are bound by multiple chromatin factors.
Moreover, depletion of these lincRNAs affects the ability of
PRC2 to regulate a specific subset of genes (27,28). More
recently, HOTAIR was also discovered to bridge several
chromatin-modifying complexes (29). Collectively, these
studies point to an emerging theme of large ncRNAs interfacing
with chromatin regulation by serving as molecular scaffolds.

It is noteworthy that chromatin-regulatory complexes are
linked with the aberrant proliferation of cancer cells. For
instance, SUZ12, a subunit of PRC2 complex is overexpressed
in colon and breast cancers and EZH2 is upregulated in many
tumors, including Hodgkin lymphoma, prostate and breast
cancer (30). Moreover, EZH2 expression is associated with
poor prognosis and is an indication for the metastatic character
of the disease (30). Besides PcG proteins, misregulation of
other chromatin complexes is associated with cancer. For
example, ~10% of leukemias bear chromosomal translocations
of the trithorax group histone methyltransferase mixed lineage
leukemia (31). Collectively, these findings point to an important
interplay between ncRNAs and chromatin regulation, which
might be relevant for the control of gene expression networks
critical for the process of cell transformation. These studies
point to the interface of RNA and chromatin representing a
new dimension in our understanding of cellular transformation.

Here we synthesize recent advances in our understanding of
large ncRNAs in cancer pathways. These include examples
with a wide range of molecular mechanisms involved in
gene regulation. Although there is a rich literature of the
roles of miRNAs and other small RNA pathways in cancer,
here we specifically focus on large ncRNAs with particular
emphasis on their molecular mechanisms in tumorigenesis.

Mechanisms of Cell Transformation  and Tumor  Suppression  by Large  ncRNAs

One of the first steps to the identification of ncRNAs relevant to
disease is the profiling of their expression across normal and
tumor samples. To this end, different profiling strategies have
been applied to identify ncRNAs in cancer. Some studies
have analyzed the available gene expression data sets in
search for tumor-specific ncRNAs (32–34). Other groups
have designed tiling arrays covering non-coding sequences of
the genome to profile tumor cells (34–36), whereas others
have focussed on the identification of ncRNA genes that are differentially
methylated in tumors and may thus have a role in cell
transformation (37,38). These approaches have led to the
identification of several long ncRNAs, whose expression and/
or DNA methylation are significantly associated with cancerous
tissues. However, this effort has been greatly limited by the
incomplete representation of non-coding sequences on DNA
microarrays. More recently, this limitation has been overcome
by the advances in massively parallel RNA sequencing combined
with new computational methods. This has allowed the
reconstruction of transcripts that originate the sequence reads
(39,40). Application of these methods can result in significant
progress in the study of currently poorly annotated ncRNAs,
such as lincRNAs, and their splicing isoform diversity.

The studies described above have identified numerous large
ncRNAs that exhibit differential expression between normal
and tumor states. Although such alterations could be due in
some cases to secondary effects of the tumor progression, numerous
experimental studies (summarized in Tables 1 and 2)
have suggested that ncRNAs play important roles in controlling
cellular pathways involved in cellular transformation, thus
acting as potential onco- or tumor-suppressor RNAs.

Table 1: Examples of large ncRNAs potentially oncogenic.

Table 1: Examples of large ncRNAs potentially oncogenic.

Table 2:  Examples of potential tumor-suppressor large ncRNAs.

A challenging task is to determine how these RNA molecules are able to
modulate those pathways. Here, we describe recent studies that
have shed new light on the functional and mechanistic roles of
large ncRNAs in cancer.

Oncogenic ncRNAs

Similar to protein-coding oncogenes, large ncRNAs can also
promote cellular pathways that lead to tumorigenesis. One
example of such an oncogenic lincRNA is HOTAIR.
HOTAIR underscores the importance of understanding the
relationship between epigenetic regulation by ncRNAs and
cancer. HOTAIR is expressed from the HOXC locus and
was initially discovered as a gene repressor of HOXD genes.
This repressive action is conferred by the interaction of
HOTAIR with the PRC2 complex, imparting PRC2 localization
and repression of the HOXD locus (22) (Fig. 1A).

Figure 1. Mechanisms of gene regulation by oncogenic large ncRNAs.

Figure 1. Mechanisms of gene regulation by oncogenic large ncRNAs.

(A) lincRNA HOTAIR recruits PRC2 to specific gene promoters for methylation
of lysine 27 of histone 3 (H3K27me), inducing gene repression that leads
to breast tumor metastasis.

(B) Large ncRNA ANRIL is transcribed antisense
of the p14/ARF and p15/CDKN2B genes. ANRIL mediates gene silencing of
the locus by interaction and recruitment of CBX7, a component of PRC1
histone 3 lysine 27-methyltransferase complex.

(C) p21 NAT ncRNA is transcribed
antisense of the p21/CDKN1A gene. This RNA requires Ago1 protein
to mediate epigenetic silencing of p21/CDKN1A promoter involving
H3K27me.

(D) The ncRNA expressed antisense of the Zeb2 gene (Zeb2
NAT) overlaps with the 5' splice site of one of Zeb2 introns. Zeb2 NAT inhibits
the splicing of the intron, which contains an IRES sequence. In this way,
Zeb2 protein translation is upregulated.

(E) Rab23 proto-oncogene (mouse)
and GAGE6 proto-oncogene (human) are repressed by PSF protein. This
repression is relieved when VL30-1 ncRNA (mouse) or MALAT-1 and
others (human) interact with PSF, displacing it from the promoter.

A new study has found that HOTAIR is significantly overexpressed
in breast tumors (34). Furthermore, HOTAIR
expression level in primary breast tumors is a powerful predictor
of patient outcomes such as metastasis and death (34). This
phenotype seems to be tightly associated with PRC2-
dependent gene repression induced by HOTAIR. Enforced
expression of HOTAIR results in an altered pattern of
H3K27 methylation and increased invasiveness, whereas the
depletion of HOTAIR causes the opposite cellular phenotype
(34). Collectively, these studies demonstrate how oncogenic
lincRNAs can hijack the epigenetic machinery to reshape
the epigenetic landscape leading to cancer.

In addition to intergenic large ncRNAs such as HOTAIR,
global transcriptome analysis shows that up to 70% of protein-coding
transcripts have antisense partners, and the perturbation
of the antisense RNA can alter the expression of the sense
gene (41). Some of these genes encode tumor-suppressor proteins
that can become epigenetically silenced by the
expression of the antisense ncRNA. Thus, misregulation of
these antisense ncRNAs could lead to cellular transformation.

Indeed, the antisense ncRNA ANRIL controls expression in
the INK4A/ARF locus comprising the tumor-suppressor genes
INK4n/ARF/INK4a, p16/CDKN2A and p15/CDKN2B, which
regulate cell cycle progression and senescence. ANRIL is transcribed
antisense to the INK4n/ARF/INK4a promoter and
overlaps with two exons of p15/CDKN2B. Independent
studies have shown that overexpression of ANRIL in prostate
cancer results in the silencing of INK4n/ARF/INK4a and p15/
CDKN2B by heterochromatin formation (42,43). ANRIL interacts
with CBX7, a component of the polycomb repressive
complex 1 (PRC1), resulting in the targeting of this complex
to the chromatin and the establishment of repressive epigenetic
marks (43) (Fig. 1B). Another example of a tumor-suppressor
gene that is epigenetically silenced by an antisense RNA is
the cell cycle regulator p21/CDKN1A. In this case, the silencing
mechanism requires the component of the RNAi pathway
Ago-1 (44) (Fig. 1C). Thus, perhaps similar to ANRIL,
the p21 antisense ncRNA may also be upregulated in cancer
rendering p21 inert, leading to cellular transformation.
In addition to the regulation of tumor-suppressor pathways
by epigenetic silencing shown by previous examples, some
antisense transcripts can also fine tune gene expression at
the post-transcriptional level. E-cadherin is a gene correlated
with gastric, breast, colorectal, thyroid and ovarian cancers.
Its loss of function is thought to contribute to progression in
cancer by increasing proliferation, invasion and/or metastasis
(45). A strong association has been demonstrated between
the expression of a particular natural antisense transcript
(NAT) and human tumors with low E-cadherin expression
(46). NAT overlaps with an intronic 5’ splice site of the
Zeb2 gene and prevents its splicing. The retained intron contains
an internal ribosome entry site (IRES) necessary for
the increased translation of Zeb2 protein, which can subsequently
function as a transcriptional repressor of E-cadherin
(46) (Fig. 1D). Collectively, these studies provide strong
impetus for further investigation of antisense ncRNAs in
cancer pathways.

Other ncRNAs can induce the expression of the protooncogene
Rab23 resulting in transformation and metastasis
of skin fibroblasts (47). These ncRNAs act as inhibitory molecules,
by complexing with the DNA and RNA-binding PSF
(polypyrimidine tract-binding protein-associated splicing
factor) protein to block its function as a transcriptional repressor,
resulting in aberrant Rab23 expression. Interestingly, the
interaction of ncRNAs with PSF is conserved between
mouse and human, although species-specific ncRNAs are
involved. In the mouse VL30-1 RNA, a member of the
VL30 family of mouse retroelement ncRNAs mediates this
mechanism (48), whereas in human five different RNAs can
interact with PSF to induce the expression of the protooncogene
GAGE6. These include the retroelements L1PA16
and MER11C, the mitochondrial gene HN encoding the
humanin peptide and the ncRNA MALAT-1 (49) (Fig. 1E).
Interestingly, many studies have identified the large ncRNA
MALAT-1 as a tumor marker that is overexpressed in many
different tumor types (35, 50,51). However, it remains to be
determined whether MALAT-1 acts exclusively through inhibition
of the tumor-suppressor PSF.

Collectively, these studies point to the possibility of ‘oncogenic
large ncRNAs’ that upon misregulation could either
silence tumor-suppressor genes or induce the expression of
oncogenes priming the cell for transformation.

Tumor-suppressor ncRNAs

Tumor-suppressor ncRNAs could phenotypically affect cells
by promoting tumor-suppressor pathways, and when their
function is compromised, cells are prone to develop cancer.
In support of this notion, a few new studies have elucidated
several examples (Table 2) of ‘tumor-suppressor large
ncRNAs’.

For example, recent studies identified numerous lincRNAs
that are induced by the p53 tumor-suppressor pathway
(17, 36). When cells are subjected to stress, the transcription
factor p53 initiates a tumor-suppressor program that involves
the expression and repression of many genes. Surprisingly,
among the genes specifically induced by p53, there are
many lincRNAs. In particular, one of these lincRNAs,
named lincRNA-p21 is directly induced by p53 to play a critical
role in the p53 transcriptional response. LincRNA-p21 is
required for the global repression of genes that interfere with
p53 function regulating cellular apoptosis. Interestingly,
lincRNA-p21 can mediate gene repression by physically interacting
with the protein hnRNP-K, allowing its localization to
promoters of genes to be repressed in a p53-dependent
manner (36) (Fig. 2).

Figure 2. Mechanisms of gene regulation by tumor-suppressor large ncRNAs.

Figure 2. Mechanisms of gene regulation by tumor-suppressor large ncRNAs.

(A) lincRNA-p21 expression is directly induced by p53. Then, lincRNA-p21
specifically interacts with hnRNP-K for localization to gene promoters for repression.

(B) GAS5 mimics the conformation of DNA GREs, binding to GR. In
this manner, GR loses the ability to activate transcription of target genes.

(C) DNA damage induces the expression of ncRNA CCND1 from the 5' of cyclin
D1/CCND1 gene. ncRNA CCND1 interacts with the TLS protein, inducing a conformational change in TLS that allows its binding to the cyclin D1 promoter.

This causes inhibition of cyclin D1 gene expression by blocking of CBP and p300 HAT activity.

GAS5 (growth arrest-specific 5) represents another example
of a large ncRNA that regulates the expression of a critical
subset of genes with tumor suppressive consequences. GAS5
is induced under starvation conditions being highly expressed
in cells whose growth is arrested (52,53). GAS5 functions by
outcompeting the DNA-binding sites of the glucocorticoid
receptor (GR), thus reducing cell metabolism (54). Specifi-
cally, the GAS5 RNA conformation mimics that of the gluticorticoid
responsive element (GRE) DNA, blocking the
ability of GR to bind gene promoters to induce their transcription
(54) (Fig. 2B). Interestingly, GAS5 has also been
observed to be downregulated in breast cancer, perhaps to
keep cancer cells active even under low nutrient conditions
(52,53).

Another tumor-suppressor ncRNA is involved in the regulation
of cyclin D1/CCND1 gene expression. Cyclin D1 is a
cell cycle regulator frequently mutated, amplified and overexpressed
in a variety of tumors (55). When cells are subjected to
DNA damage, ncRNAs are expressed from the 5’ regulatory
regions of cyclin D1 gene, thereby mediating its transcriptional
repression. Indeed, these ncRNAs interact with the
TLS protein, inducing its allosteric modification. This conformational
change allows the association of TLS to the cyclin
D1 promoter, which inhibits transcriptional induction by
histone acetyltransferases such as CBP and p300 (56)
(Fig. 2C).

These studies show that tumor-suppressor ncRNAs can be
rapidly induced by cellular stress to regulate gene expression.
Possibly, RNA molecules, due to their quick turn over rate, are
ideal effectors when a rapid response is required to protect
cells from external insults.

Future Perspectives:

The studies reviewed herein contribute to the growing evidence
of the important roles of large ncRNAs in cancer,
both by regulating tumor-suppressor and oncogenetic pathways.
Thus, some ncRNAs play a critical role in maintaining
cellular homeostasis and, when we have a deeper understanding
of their roles in cancer, they can be used as diagnostic tools
in conjunction with protein-coding genes.

An intriguing common theme is emerging of large ncRNAs
forming ribonucleic–protein complexes that impart key regulatory
functions in cellular circuits. We have discussed
HOTAIR, lincRNA-p21 ANRIL or MALAT-1 among others
that share a common functionality of forming RNA–protein
complexes with chromatin regulatory factors. However, a
higher-resolution understanding of cancer will require a comprehensive
identification of large ncRNAs misregulated across
a spectrum of cancer types and their associated protein complexes.
Both biochemical approaches combined with in vivo
studies will be required to fully understand the mechanistic
and phenotypic roles of large ncRNAs in cancer.

A key goal for future progress is to identify large ncRNAs
that could potentially serve as biomarkers for specific disease
states. A clear advantage in the diagnostic use of ncRNA
detection versus that of protein-coding RNAs is that in the
former the RNA itself is the effector molecule, thus its
expression levels may be a better indicator of the intrinsic
characteristics of the tumor. Indeed, microRNA expression
profiling has been successfully used for cancer classification,
reflecting the developmental lineage and differentiation state
of the tumors (10–12). In the near future, the great technological
advance and decrease in cost of parallel massive sequencing
will allow the profiling of the entire transcriptome of
every type of tumor, including small and large ncRNA molecules,
allowing the most powerful and informative diagnosis.
In fact, the application of the new genomic technologies to the
profiling of multiple cancers is already a reality. The tremendous
amount of data generated by these projects present great
possibilities for prognosis and therapeutic application. This
has called for the creation of the International Cancer
Genome Consortium (ICGC) that will coordinate the international
effort to systematically study more than 25 000
cancer genomes at the genomic, epigenomic and transcriptomic
levels (57). We can easily predict that in the next few
years a complete catalogue of the large ncRNA expression
as well as the genetic mutations, amplifications and deletions
in non-coding regions associated with different types of
tumors will be available.

Besides the imminent use of our knowledge of cancer-associated
large ncRNAs for diagnosis, therapeutic applications
may be possible in a more distant future. The progress
in the use of RNAi-mediated gene silencing for the treatment
of different diseases is encouraging and could be applied
to selectively silence oncogenic ncRNAs. Gene therapy
could also be applied for the delivery to specific cells of
tumor-suppressor large ncRNAs for the treatment of cancer.
However, many technical challenges have to be overcome
for a wider use of therapeutic RNAi and gene therapy, including
the development of reliable delivery systems, dosage
regimes and techniques to ameliorate RNAi off target effects
(58,59). When the technical limitations are overcome,
ncRNAs may be ideal targets for therapy due to their high
turnover rate as well as their direct and specific regulatory
functions. Predictably, therapeutic targeting of ncRNAs will
carry fewer negative effects than those of protein-coding
genes, given that they function regulating specific facets of
their protein interacting partners.

In summary, overwhelming evidence reveals that large
ncRNAs are molecules that keep in perfect tune the balance
of gene expression networks, and discordance in their function
results in homeostatic imbalance, ultimately causing cellular
transformation. Large ncRNAs are shedding new light on
our understanding of these cancer pathways and may represent
a ‘missing link’ in cancer.

Acknowledgements:

We would like to thank Moran Cabili-Kalmar, Magdalena J. Koziol, Sabine Loewer and Ba´rbara Tazo´n-Vega for critical comments on the manuscript and Sigrid Hart (Broad Institute) for illustration support.

Conflict of Interest statement.
None declared.

Funding:

J.L.R. is a Damon Runyon-Rachleff, Searle and Smith Family Foundation Scholar and Richard Merkin awardee. M.H. is supported by the NIH Directors New Innovator Award (Grant number 1DP2OD00667-01), Smith Family Foundation, the Damon Runyon Cancer Foundation and Searle Scholar Program.

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In this detailed review by Maite Huarte and  John Rinn, we find early evidence of long  ncRNAs ( >200 nucleotides ) that are associated with either oncgene activation or suppression, are bridging (in trans) widespread gene loci, and are closely associated with antisense epigenetic states within metastatic neoplasms. Earlier studies had revealed long ncRNAs to be synthesized as  intergenic (between genes), intragenic/intronic (within genes), and/or antisense. ncRNAs ranging between 50-200 nucleotides are under intense study.

RNA Biol. 2010 Sep 2, 7(5) [Epub ahead of print], PMID: 20931598]
http://www.landesbioscience.com/journals/rnabiology/article/13216/

"Long noncoding RNA in genome regulation: Prospects and mechanisms".

Hung T, Chang HY.

Howard Hughes Medical Institute and Program in Epithelial Biology,
Stanford University School of Medicine, Stanford, CA, USA. 94305

Abstract:
Long noncoding RNAs (lncRNAs) are pervasively transcribed and critical regulators of the epigenome. (1,2) These long, polyadenylated RNAs do not code for proteins, but function directly as RNAs, recruiting chromatin modifiers to mediate transcriptional changes in processes ranging from X-inactivation (XIST) to imprinting (H19). (3) The recent discovery that lncRNA HOTAIR can link chromatin changes to cancer metastasis (4) furthers the relevance of lncRNAs to human disease. Here, we discuss lncRNAs as regulatory modules and explore the implications for disease pathogenesis.

1. Each cell retains all of its embryonic genes for a lifetime.

2. Controls for embryonic genes are often absent in adults.

3. Uncontrolled embryonic genes can replicate wildly.

4.  Replicating genes participate in  intra-cellular competition.

5.  The basis for gene competition is selective transcription.

6.  MicroRNAs can reprogram embryomic transcription.

7.  Gene reprogramming can produce normal phenotypes.

8.  Normal phenotypes can by-pass chromosomal lesions.

9.  MicroRNA therapy may need to be permanent.

10. Transplantation of microRNAs could be preferred.

http://www.embryomas.net/

1. Pathways within cell genomes involve a flow of information.

2. Information can flow by direct contact or by third parties.

3. Direct contact within whole genomes is difficult to regulate.

4. DNA-DNA direct contects are influenced by agents.

5. Nuclear agents include hydrophilic ionic and hydrophobic conforming ligands.

6. Third parties within genomes involve RNAs and proteins.

7.  RNAs and proteins are easy to regulate or reverse.

8.  Information can be shared, lost, or transformed.

9. System information can be hidden during system isolation.

10.  Local information can be permanently lost during system entropy.

http://www.cancerbiophysics.net

Links to Current Research in Euchromatin:
Links to Euchromatin Activator RNA Reviews:
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Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:
Links to Selective Gene Transcription:
Links to RNA-Induced Epigenetics:
Links to RNA-Induced Embryogenesis:
Links to RNA and Biological Causality:
Links to Reprogramming and Neoplasia:

A Brief History of Activator RNA:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".
(PowerPoint Presentation).

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