Subnuclear domain proteins in cancer cells support transcription factor RUNX2 functions in DNA damage response

Yang, Seungchan; Quaresma, Alexandre J.C.; Nickerson, Jeffrey A.; Green, Karin M.; Shaffer, Scott A.; Martin-Buley, Lori A.; Lian, Jane B.; Stein, Janet L.; Wijnen, André J. van

doi:10.1242/jcs.160051

Cited by 22 publications

(19 citation statements)

References 58 publications

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“…Of particular interest, many RUNX2 target genes involved in cell migration, adhesion, and proliferation are upregulated upon WWOX loss in human OS (27). Proteomic studies recently showed that RUNX2 forms functional complexes with several proteins to mount an integrated response to DNA damage (39). Our results lead us to speculate that WWOX has differential effects on RUNX2 binding at promoters of selected genes.…”

Section: Discussionmentioning

confidence: 99%

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

et al. 2016

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Osteosarcoma (OS) is a highly metastatic form of bone cancer in adolescents and young adults which is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in pre-osteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human OS in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared to mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared to p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated OS. The Wwox;p53Δosx1 double knockout establishes a new OS model with significant advancement over existing models.

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Section: Discussionmentioning

confidence: 99%

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

et al. 2016

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“…important inhibitor of estrogen signaling and stimulates oncogenic pathways. RUNX2 is a transcription factor involved in regulating cell determination (Young et al 2007;Blyth et al 2010) and the TGF-β and Wnt/β-catenin pathways (which are also involved in cancer development, progression, and metastasis) (Young et al 2007;Yang et al 2015) and opposes ER signaling, leading to more aggressive ER + breast cancer (Tandon et al 2014). Interestingly, recent studies have also shown that RUNX2 plays a crucial role in regulating mammary stem cell regeneration (Ferrari et al 2015).…”

Section: Identification Of Mrnas Highly Dependent On Overexpression Omentioning

confidence: 99%

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

et al. 2017

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The majority of breast cancers expresses the estrogen receptor (ER) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER breast cancer through selective mRNA translational reprogramming.

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“…Recently, we have also observed a similar phenomenon under 2D cultures demonstrating that depletion of RUNX2 in MiaPaCa-2 cells increased the accumulation of γH2AX following GEM or SAHA exposure (14,31), indicating that RUNX2 attenuated the expansion of DNA lesions irrespective of 2D or 3D culture systems. Notably, Yang et al (32) described that RUNX2 binds to γH2AX and siRNA-mediated knockdown of RUNX2 increases γH2AX in response to UV. Further studies are required to elucidate the functional significance of RUNX2/γH2AX interaction during DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

et al. 2018

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Recently, it has been well‑recognized that the response toward anticancer drugs differs between two‑ and three‑dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53‑mutated pancreatic cancer MiaPaCa‑2 cells. According to our results, MiaPaCa‑2 cells, but not p53‑wild‑type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum‑free sphere‑forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa‑2 spheres accompanied by the transcriptional activation of p53 family‑target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro‑apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM‑mediated cell death of MiaPaCa‑2 spheres compared to that of non‑depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM‑induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa‑2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation.

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Subnuclear domain proteins in cancer cells support transcription factor RUNX2 functions in DNA damage response

Cited by 22 publications

References 58 publications

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

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