Zhang Z et al. (2017), Similarity in gene-regulatory networks suggests...

XB-ART-53787

J Biol Chem 2017 Aug 04;29231:12842-12859. doi: 10.1074/jbc.M117.785865.

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Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells.

Zhang Z , Lei A , Xu L , Chen L , Chen Y , Zhang X , Gao Y , Yang X , Zhang M , Cao Y .

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Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and redifferentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that inhibition of the epigenetic modification enzyme enhancer of zeste homolog 2 (EZH2), histone deacetylases 1 and 3 (HDAC1 and -3), lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines. The regulatory effect of these enzymes in neuronal differentiation resided in their intrinsic activity in embryonic neural precursor/progenitor cells. We further found that a major part of pan-cancer-promoting genes and the signal transducers of the pan-cancer-promoting signaling pathways, including the epithelial-to-mesenchymal transition (EMT) mesenchymal marker genes, display neural specific expression during embryonic neurulation. In contrast, many tumor suppressor genes, including the EMT epithelial marker gene that encodes cadherin 1 (CDH1), exhibited non-neural or no expression. This correlation indicated that cancer cells and embryonic neural cells share a regulatory network, mediating both tumorigenesis and neural development. This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells.

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Species referenced: Xenopus laevis
Genes referenced: ahr akt1 akt2 apc arid1a axin1 axl bcl9 birc5l brms1 casp9 cbl ccnd1 cdh1 cdh2 cdk1 cdkn1a cdkn1b cdkn2b cdt1 chfr cnp crk ctnnb1 ddx5 dek dlc1 dmbt1 dnmt1 dot1l dyrk1a.2 e2f1 ehmt2 eif3c eif4g1 ezh2 gas1 hdac1 hdac2 hdac3 hexim1 hgf hic1 hras itk jak2 kdm1a kdm3a kdm4a kdm5b krasl krt12.4 mcam mgmt msi1 mta1 nes npb nppa nras nsd2 ogt pbrm1 pcna pdcd4 perp phlpp1 pik3ca pim1 pkm plk1 ppm1d prkaa1 prkaa2 prmt1 prmt5 pten ptgs2 ptk2 rad21 raf1 ret rheb setd1a setdb1 slc16a1 smad1 smad2 smad4 snai1 snd1 sox2 st13 stat3.2 stoml2 tert tet2 tgfbr1 tk1 tmem97 top1 top2a tp53 tp53bp2 tp73 txnip ube2c usp39 usp7 vav2 vim xpo1 yy1 zeb1 zeb2
GO keywords: neurogenesis

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	FIGURE 6. The genes involved in tumorigenesis show tissue-specific expression in Xenopus embryos. A, whole mount in situ hybridization (WMISH) detection of expression of genes coding for chromatin modification enzymes. B, WMISH detection of expression of EMT marker genes. Expression of xk81a1 and sox2 is shown as controls. Mid- to late neurula and tailbud embryos were used. Typical expression domains are labeled but the same expression domain in different panels may not be labeled repeatedly. Each embryo is oriented with the anterior to the left. Dorsal view is shown for neurula embryos, and lateral view is shown for tailbud, with dorsal side to the top of each panel. A, anterior; ba, branchial arch; df, dorsal fin; ep, epidermis; ev, ear vesicle; ey, eye; fb, forebrain; hb, hindbrain; he, heart; mb, midbrain; nc, neural crest; np, neural plate; nt, neural tube; P, posterior; pcv, posterior cardinal vein; pl, plexus; pn, pronephros; sc, spinal cord; tb, tailbud.
	FIGURE 7. Neural specific expression of genes promoting or being upregulated/activated during cancer development/progression. Expression patterns were examined with WMISH. Embryos at the same stages as in Fig. 6 were used. Embryo orientation is the same as in Fig. 6. Typical expression domains are labeled but the same expression domain in different panels may not be labeled repeatedly. A, anterior; ad, adenohypophysial placode; ba, branchial arch; cgp, cement gland primordium; ev, ear vesicle; ey, eye; fb, forebrain; hb, hindbrain; he, heart; mb, midbrain; np, neural plate; P, posterior; pd, pronephric duct; sm, somite.
	FIGUTRE 8. Genes repressing or being downregulated during cancer development/progression show varied expression patterns in Xenopus embryos. A, spatial expression patterns were examined with WMISH. Embryos at the same stages as shown in Fig. 6 were used and presented in the same way as in Fig. 6. A, anterior; ad, adenohypophysial placode; ba, branchial arch; cg, cement gland; cgp, cement gland primordium; ep, epidermis; ev, ear vesicle; ey, eye; fb, forebrain; hb, hindbrain; le, lens; mb, midbrain; mhb, midbrain-hindbrain boundary; nc, notochord; nu, neuron; np, neural plate; nt, neural tube; P, posterior; pn, pronephros; pm, paraxial mesoderm; ps, posterior somite; sm, somite; tg, trigeminal nerve. B, summary of the relatedness of gene expression/function in cancer and their expression.
	FIGURE S5. Genes involved in cancer show different patterns of expression. A, spatial expression of genes that promote or are upregulated during cancer development/progression. B, spatial expression of genes that can play dual roles (promote or are upregulated in some cancer types while repress or are downregulated in some other types) during the development/progression of different cancer types. Each embryo is oriented with the anterior to the left. Dorsal view is shown for neurula embryos, and lateral view is shown for tailbud, with dorsal side to the top of each panel. Typical expression domains are labeled but the same expression domain in different panels may not be labeled repeatedly. A, anterior; ad, adenohypophysial placode; anp, anterior neural plate; anpb, anterior neural plate border; ba, branchial arch; cg, cement gland; cgp, cement gland primordium; cnh, chordoneural hinge; cnp, chordal neural plate; d, dorsal view; ep, epidermis; ev, ear vesicle; ey, eye; fb, forebrain; hb, hindbrain; l, lateral view; mb, midbrain; ng, neural groove; np, neural plate; npb, neural plate border; P, posterior; pd, pronephric duct; pm, paraxial mesoderm; ps, posterior somite; sc, spinal cord; sm, somite; tg, trigeminal nerve.

References [+] :

Aiello, Echoes of the embryo: using the developmental biology toolkit to study cancer. 2016, Pubmed