A long non-coding RNA molecule called cherub is a driver of tumor development.
How healthy cells become tumors is a question that has interested scientists for decades. Many tumors exhibit genomic instability – that is, increased numbers of DNA mutations and chromosomal rearrangements. However, some tumors – including most childhood cancers – have few mutations and are thought to be driven by mechanisms other than genomic instability (Lee et al., 2012).
Important cancer research in flies has been carried out using neural stem cells called neuroblasts. Normally, a type of neuroblast called a Type II neuroblast divides asymmetrically to form a new neuroblast and a slightly more specialized cell type called an intermediate neural progenitor cell (INP); the new neuroblast is able to repeat this process several times. In parallel, the INP continues to divide to produce a new INP and a neuronal precursor cell in each round (Bello et al., 2008; Boone and Doe, 2008; Bowman et al., 2008, Figure 1A). The neuronal precursor then divides to generate mature neurons. When a tumor suppressor gene called brat is blocked, INPs transform back into tumor neuroblasts that divide indefinitely (Lee et al., 2006). So far, the mechanisms involved have remained unclear.
Now, in eLife, Jürgen Knoblich and colleagues at the IMBA in Vienna and the University of Basel – including Lisa Landskron as first author – report that genomic instability is not a driver of neuroblast tumors (Landskron et al., 2018). Landskron et al. compared healthy flies and flies in which the brat gene had been mutated and showed that both groups of flies had the same number of chromosomes. Moreover, they found no additional DNA mutations responsible for tumor development.
However, further analyzes revealed that the tumor cells had increased levels of a previously uncharacterized long non-coding RNA: this is a molecule that is transcribed from DNA but is not usually translated into protein. Landskron et al. found that this specific long non-coding RNA, which they named cherub, was not required for normal development, as mutant flies lacking cherub were healthy and fertile. However, flies with a defect in both the brat gene and the cherub gene had smaller tumors, which suggests that cherub is required for tumor progression.
While other long non-coding RNAs have been implicated in tumor growth, cherub is the first to be discovered that is not uniformly distributed throughout the cell. Rather, cherub is located at the basal end of the neuroblast cell membrane. When healthy neuroblasts divide, cherub is distributed into the INP, which forms on the basal side of the neuroblast, and then diffuses throughout the cell. Thus, with each round of division, cherub levels slowly decrease in the INP (Figure 1A). In brat mutants, however, cherub remains at the cell membrane in both the neuroblast and in the INP. This faulty localization prevents the dilution of cherub and causes the INP to transform back into a tumor neuroblast (Figure 1B).
Why does the incorrect localization of cherub cause tumor growth? In fly neuroblasts, the proteins Imp and Syncrip regulate neuroblast aging (Ren et al., 2017). Normally, these two proteins inhibit each other: Syncrip levels increase as the neuroblasts age, while Imp levels decrease. Both the expression of Syncrip and the absence of Imp are required for neuroblasts to stop dividing (Yang et al., 2017, Figure 1A).
Landskron et al. showed that in flies lacking brat, Syncrip and cherub are inappropriately localized at the tumor neuroblast cell membrane. Moreover, Syncrip and Imp are both expressed. This is presumably because newly-produced Syncrip remains tethered to cherub at the cell membrane, where it is unable to reduce Imp levels (Figure 1B). Thus, the tumors continually produce Imp and do not age. When cherub is not present, Syncrip remains distributed throughout the cell. This reduces the levels of Imp which, in turn, slows the growth of any tumor and improves the life expectancy of brat mutant flies (Figure 1C). How does cherub localize to the cell membrane? The experiments revealed that cherub binds to another protein called Staufen, which attaches to the asymmetric cell division machinery, and thus tethers both cherub and Syncrip to the cell membrane.
This work reinforces the notion that changes to the proteins that regulate asymmetric cell division and cell fate can drive tumor formation. Previous research has shown that Imp levels are also dependent on another protein called Chinmo, and that overexpression of Chinmo causes tumor growth by maintaining inappropriately high Imp levels during the window when Imp is normally expressed (Narbonne-Reveau et al., 2016). Thus, preventing stem cells from maturing and aging appears to fuel tumor development.
This study also highlights the importance of long non-coding RNAs in stem cell development and in tumor formation. While it has been shown that other long non-coding RNAs are involved in stem cell development, this may be one of the first examples where changing the localization of such molecules prevents stem cells from aging, thus driving tumor growth (Guttman et al., 2011). It will be interesting to see whether other long non-coding RNAs use the same mechanisms to drive tumorigenesis.
Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cellsDevelopmental Neurobiology 68:1185–1195.https://doi.org/10.1002/dneu.20648
A remarkably simple genome underlies highly malignant pediatric rhabdoid cancersJournal of Clinical Investigation 122:2983–2988.https://doi.org/10.1172/JCI64400
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy.
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.