Meta‐analysis of expression of l(3)mbt tumor‐associated germline genes supports the model that a soma‐to‐germline transition is a hallmark of human cancers

Feichtinger, Julia; Larcombe, Lee; McFarlane, Ramsay J.

doi:10.1002/ijc.28577

Cited by 29 publications

(26 citation statements)

References 46 publications

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“…Interestingly, preventing expression of certain germ-line genes, including vasa and piwi, prevented development of these tumors, suggesting that certain germ-line gene products promote tumor formation and/or growth. Recently, the human homologs of these germ-line genes were found to be expressed in a wide variety of human cancers, including ovarian and brain cancers (29). Although cancer cells may hijack the mechanisms used by germ cells to proliferate and survive, other cells, such as the somatic cells in C. elegans, are negatively affected by expression of germ-line proteins.…”

Section: Discussionmentioning

confidence: 99%

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Knutson

Rechtsteiner

Strome

2016

Proc. Natl. Acad. Sci. U.S.A.

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The germ lineage is considered to be immortal. In the quest to extend lifespan, a possible strategy is to drive germ-line traits in somatic cells, to try to confer some of the germ lineage's immortality on the somatic body. Notably, a study in Caenorhabditis elegans suggested that expression of germ-line genes in the somatic cells of long-lived daf-2 mutants confers some of daf-2's long lifespan. Specifically, mRNAs encoding components of C. elegans germ granules (P granules) were up-regulated in daf-2 mutant worms, and knockdown of individual P-granule and other germ-line genes in daf-2 young adults modestly reduced their lifespan. We investigated the contribution of a germ-line program to daf-2's long lifespan and also tested whether other mutants known to express germ-line genes in their somatic cells are long-lived. Our key findings are as follows. (i) We could not detect P-granule proteins in the somatic cells of daf-2 mutants by immunostaining or by expression of a P-granule transgene. (ii) Whole-genome transcript profiling of animals lacking a germ line revealed that germ-line transcripts are not up-regulated in the soma of daf-2 worms compared with the soma of control worms. (iii) Simultaneous removal of multiple P-granule proteins or the entire germ-line program from daf-2 worms did not reduce their lifespan. (iv) Several mutants that robustly express a broad spectrum of germ-line genes in their somatic cells are not long-lived. Together, our findings argue against the hypothesis that acquisition of a germ-cell program in somatic cells increases lifespan and contributes to daf-2's long lifespan.germ line | aging | C. elegans | daf-2 | P granules G erm and soma are the two most fundamentally different cell types found in multicellular organisms (1). Germ cells are totipotent and constitute the only immortal lineage, capable of generating entire new organisms generation after generation, whereas somatic cells differentiate into specialized cell types and are mortal, senescing and dying each generation. Maintaining the proper identity of these cell types is essential for propagation of species, and molecular barriers at both the transcriptional and translational levels have evolved to ensure the germ-soma distinction (1). Removal of these barriers in germ cells can lead to both expression of somatic factors and sterility (2-4), whereas removal of these barriers in somatic cells is associated with reentry into the cell cycle and cancer (5, 6). Despite these barriers, it is unknown whether some cell types can tolerate partial fate switching and perhaps adopt traits of other cell types to benefit the organism.An attractive possibility is that acquisition of a germ-cell program by the somatic body can capture some of the immortality of the germ lineage and extend lifespan (7,8). Indeed, a study in Caenorhabditis elegans supports that possibility (9). In C. elegans, inhibition of the insulin-like signaling pathway by a mutation in daf-2 doubles lifespan through activation of the FOXO transcription factor DAF-16...

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Section: Discussionmentioning

confidence: 99%

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Knutson

Rechtsteiner

Strome

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, there is emerging evidence that they play a functional role in initiating and maintaining oncogenesis. The requirement for tumor initiation is eluded to by the finding that l (3)mbt brain tumor formation in Drosophila required the activation of germline genes (17), a gene activation profile that is also found in many human cancers (18). Indeed, this has led to the proposal that a key feature of oncogenesis is the cellular switch from a specific somatic designation to the acquisition of a germline cell-like state, the so called "soma-to-germline transition," which reflects the functional activation of germline-specific genes to meet the needs of the evolving oncogenic process in a stage-and environment-specific context (18).…”

Section: Activation Of Meiotic Functions In Cancer Cellsmentioning

confidence: 99%

Meiosis-like Functions in Oncogenesis: A New View of Cancer

McFarlane

Wakeman

2017

Cancer Research

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Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 5712–6. ©2017 AACR.

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“…Drosophila, where mutations in this gene lead to the development of optical neural ganglion malignant tumors in late third instar larvae, with a terminal phenotype preceding pupation (1,2). L(3)mbt homologs are found throughout the phylogenetic tree, including humans, where hL(3)MBTL1 has been correlated with several types of cancer (3)(4)(5). L(3)mbt contains three repeated sequence elements dubbed MBT repeats, the presence of which is a common feature shared by the MBT large family of proteins (reviewed in ref.…”

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confidence: 99%

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

Blanchard

Georlette

Antoszewski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lethal malignant brain tumors (lmbt) result from the loss of the conserved transcriptional repressor l(3)mbt, in Drosophila melanogaster. Similar mutations in the human homolog L3MBTL1 correlate with some cancers. The protein's C-terminal MBT repeats bind mono and dimethylated histones in vitro, which could influence recruitment of L3MBTL1 to its target sites. The L(3)mbt chromatin targeting mechanism, however, is controversial and several studies suggest insufficiency or a minor role for histone methylation in determining the site specificity for recruitment. We report that L(3)mbt colocalizes with core members of the Myb-MuvB/DREAM (MMB/DREAM) transcriptional regulatory complex genome-wide, and that L(3)mbt-mediated repression requires this complex in salivary glands and larval brains. Loss of l(3)mbt or of MMB components through mutation cause similar spurious expression of genes, including the transposon regulatory gene piwi, in terminally differentiated cells. The DNA-binding MMB core component Mip120 (Lin54) is required for L(3)mbt recruitment to chromosomes, whereas Mip130 (Lin9) (an MMB core protein) and E2f2 (an MMB transcriptional repressor) are not, but are essential for repression. Cytolocalization experiments suggest the presence of sitespecific differential composition of MMB in polytene chromosomes where some loci were bound by a Myb-containing or alternatively, an E2f2 and L(3)mbt form of the complex.epigenetics | bar coding | tumorigenesis

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Meta‐analysis of expression of l(3)mbt tumor‐associated germline genes supports the model that a soma‐to‐germline transition is a hallmark of human cancers

Cited by 29 publications

References 46 publications

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Meiosis-like Functions in Oncogenesis: A New View of Cancer

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

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