Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer

Roca, Hernán; Hernandez, James R.; Weidner, Savannah; McEachin, Richard C.; Fuller, David; Sud, Sudha; Schumann, Taibriana; Wilkinson, John E.; Zaslavsky, Alexander; Li, Hangwen; Maher, Christopher A.; Daignault‐Newton, Stephanie; Healy, Patrick; Pienta, Kenneth J.

doi:10.1371/journal.pone.0076773

Cited by 239 publications

(278 citation statements)

References 37 publications

(63 reference statements)

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“…On the other hand, IP6K2 is a downstream target of the Wnt/β-catenin signaling pathway and participates in its oncogenic activities (38). Moreover, IP6K2 is down-regulated by transcription factors that promote mesenchymal-epithelial transition (39) and by tumor suppressors that inhibit EMT (40). This suggests that IP6K2 promotes mesenchymal processes, consistent with a role in tumor metastasis.…”

Section: Discussionmentioning

confidence: 81%

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

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

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The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.I nositol pyrophosphates, conserved eukaryotic messenger molecules with a pyrophosphate bond, mediate numerous physiologic processes including regulation of Akt (1), insulin secretion (2), ATP production (3), DNA repair (4), and damage response (5). Exemplified by diphosphoinositol pentakisphosphate (PPIP5, IP7), inositol pyrophosphates are primarily generated by a family of three inositol hexakisphosphate (IP6) kinases (IP6K) (6, 7) and also may be formed by a more recently described group of IP6/7 kinases (8). IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.Tumor cell metastasis requires loss of cell-cell adhesion and gain of migratory and invasive properties, a collective program known as epithelial-mesenchymal transition (EMT), which is also critical for embryonic development (13). Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20). As a master kinase controlling the activity of AMPK and 13 other AMPK-like kinases (21), LKB1 mediates diverse cellular processes such as polarity, adhesion, metabolism, tumor growth/metastasis, and neuronal axon initiation/branching (22). Unlike conventional protein kinases, LKB1 is not activated by activation loop phosphorylation but by protein-protein interaction with two other subunits of the heterotrimeric holoenzyme: STRAD and Mo25. LKB1 can also exist as an inactive nuclear monomer. STRAD binds and stabilizes LKB1 (23) in the cytosol, where it is phosphorylated at serine 428 by PKCζ (24). Whether cytosolic localization enhance...

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Section: Discussionmentioning

confidence: 81%

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

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

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“…Future theoretical studies of the circuits studying EMT and stemness should consider the effect of activation of OCT4 by miR-200 [17], inhibition of EMT by let-7 through HMGA2 [36] and mutual inhibition between ZEB1/2 and MET-inducing transcription factor OVOL1/2 [61], all of which can introduce feedback loops in the regulatory circuit we analysed and affect its dynamics.…”

Section: Discussionmentioning

confidence: 99%

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

Jolly

Huang

et al. 2014

J. R. Soc. Interface.

178

166

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Epithelial cells undergoing epithelial-to-mesenchymal transitions have often been shown to behave as cancer stem cells, but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit and LIN28 is inhibited by miR-200, coupling the two modules. Here, using a specially devised theoretical framework to investigate the dynamics of the LIN28/let-7 system, we show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/ mesenchymal (E/M) phenotype. We find significant correspondence between the existence of the three states of the two circuits: E-D, M-U and E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (when compared with either the E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kB and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M phenotype to gain stemness. Our results are consistent with emerging concept that partial EMT can lead to stemness.

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“…Ovol2 expression correlates with hallmark genes of epithelial differentiation in cancer cell lines. 28 Therefore, we decided to further investigate the potential functional role of Ovol2 downstream of GRHL2. Downregulation of Ovol2 and H3K4 trimethylation at the Ovol2 promoter in Grhl2-KD cells and GRHL2-binding to the Ovol2 promoter in IMCD-3 cells were validated by quantitative RT-PCR and ChIP-quantitative PCR, respectively ( Figure 5, A-C).…”

Section: Grhl2 Is Required For Lumen Expansion and Epithelial Barriermentioning

confidence: 99%

A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion

Aue

Hinze

Walentin

et al. 2015

Journal of the American Society of Nephrology

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Grainyhead transcription factors control epithelial barriers, tissue morphogenesis, and differentiation, but their role in the kidney is poorly understood. Here, we report that nephric duct, ureteric bud, and collecting duct epithelia express high levels of grainyhead-like homolog 2 (Grhl2) and that nephric duct lumen expansion is defective in Grhl2-deficient mice. In collecting duct epithelial cells, Grhl2 inactivation impaired epithelial barrier formation and inhibited lumen expansion. Molecular analyses showed that GRHL2 acts as a transcriptional activator and strongly associates with histone H3 lysine 4 trimethylation. Integrating genome-wide GRHL2 binding as well as H3 lysine 4 trimethylation chromatin immunoprecipitation sequencing and gene expression data allowed us to derive a high-confidence GRHL2 target set. GRHL2 transactivated a group of genes including Ovol2, encoding the ovo-like 2 zinc finger transcription factor, as well as E-cadherin, claudin 4 (Cldn4), and the small GTPase Rab25. Ovol2 induction alone was sufficient to bypass the requirement of Grhl2 for E-cadherin, Cldn4, and Rab25 expression. Re-expression of either Ovol2 or a combination of Cldn4 and Rab25 was sufficient to rescue lumen expansion and barrier formation in Grhl2-deficient collecting duct cells. Hence, we identified a Grhl2/Ovol2 network controlling Cldn4 and Rab25 expression that facilitates lumen expansion and barrier formation in subtypes of renal epithelia. The renal collecting duct's vital electrolyte and waterregulatory functions are carried out by highly specialized cell populations. 1 The collecting duct itself is composed of a tight epithelium, which separates the urinary compartment from a hypertonic interstitium and maintains a barrier to concentration gradients. The collecting duct derives from the ureteric bud, which emanates from the nephric duct and then undergoes branching morphogenesis in response to signals from the adjacent metanephric mesenchyme. 2 Many of the genes that are critical for aspects of nephric duct development continue to be expressed in the ureteric bud and collecting duct, serving roles in development, differentiation, and maintenance of these cells (e.g., Pax2/8, Gata3, Emx2, and Hnf1b). 3 Little is known about the molecular pathways governing the specific epithelial properties of these cells, although it is clear that these epithelia share several cell biologic properties such as a uniform tubular appearance characterized by a cuboidal epithelium surrounding a fluid-filled lumen and a molecular composition of the apical junctional complex that includes

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Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer

Cited by 239 publications

References 37 publications

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion

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