Transcriptional regulation by RUNX3

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R-HSA-8878159
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Pathway
Species
Homo sapiens
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The transcription factor RUNX3 is a RUNX family member. All RUNX family members, RUNX1, RUNX2 and RUNX3, possess a highly conserved Runt domain, involved in DNA binding. For a more detailed description of the structure of RUNX proteins, please refer to the pathway 'Transcriptional regulation by RUNX1'. Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta). Studies in mice have shown that RUNX3 plays a role in neurogenesis and development of T lymphocytes. RUNX3 is implicated as a tumor suppressor gene in various human malignancies.
During nervous system formation, the Cbfb:Runx3 complex is involved in development of mouse proprioceptive dorsal root ganglion neurons by regulating expression of Ntrk3 (Neurotrophic tyrosine kinase receptor type 3) and possibly other genes (Inoue et al. 2002, Kramer et al. 2006, Nakamura et al. 2008, Dykes et al. 2011, Ogihara et al. 2016). It is not yet known whether RUNX3 is involved in human neuronal development and neuronal disorders.
RUNX3 plays a major role in immune response. RUNX3 regulates development of T lymphocytes. In mouse hematopoietic stem cells, expression of Runx3 is regulated by the transcription factor TAL1 (Landry et al. 2008). RUNX3 promotes the CD8+ lineage fate in developing thymocytes. In the CD4+ thymocyte lineage in mice, the transcription factor ThPOK induces transcription of SOCS family members, which repress Runx3 expression (Luckey et al. 2014). RUNX3, along with RUNX1 and ETS1, is implicated in regulation of transcription of the CD6 gene, encoding a lymphocyte surface receptor expressed on developing and mature T cells (Arman et al. 2009). RUNX3 and ThPOK regulate intestinal CD4+ T cell immunity in a TGF-beta and retinoic acid-dependent manner, which is important for cellular defense against intestinal pathogens (Reis et al. 2013). Besides T lymphocytes, RUNX3 is a key transcription factor in the commitment of innate lymphoid cells ILC1 and ILC3 (Ebihara et al. 2015). RUNX3 regulates expression of CD11A and CD49D integrin genes, involved in immune and inflammatory responses (Dominguez-Soto et al. 2005). RUNX3 is involved in mouse TGF-beta-mediated dendritic cell function and its deficiency is linked to airway inflammation (Fainaru et al. 2004).
In addition to its developmental role, RUNX3 is implicated as a tumor suppressor. The loss of RUNX3 expression and function was first causally linked to the genesis and progression of human gastric cancer (Li et al. 2002). Expression of RUNX3 increases in human pancreatic islet of Langerhans cells but not in pancreatic adenocarcinoma cells in response to differentiation stimulus (serum withdrawal) (Levkovitz et al. 2010). Hypermethylation of the RUNX3 gene is associated with an increased risk for progression of Barrett's esophagus to esophageal adenocarcinoma (Schulmann et al. 2005). Hypermethylation-mediated silencing of the RUNX3 gene expression is also frequent in granulosa cell tumors (Dhillon et al. 2004) and has also been reported in colon cancer (Weisenberger et al. 2006), breast cancer (Lau et al. 2006, Huang et al. 2012), bladder cancer (Wolff et al. 2008) and gastric cancer (Li et al. 2002). In colorectal cancer, RUNX3 is one of the five markers in a gene panel used to classify CpG island methylator phenotype (CIMP+) (Weisenberger et al. 2006).
RUNX3 and CBFB are frequently downregulated in gastric cancer. RUNX3 cooperates with TGF-beta to maintain homeostasis in the stomach and is involved in TGF-beta-induced cell cycle arrest of stomach epithelial cells. Runx3 knockout mice exhibit decreased sensitivity to TGF-beta and develop gastric epithelial hyperplasia (Li et al. 2002, Chi et al. 2005). RUNX3-mediated inhibition of binding of TEADs:YAP1 complexes to target promoters is also implicated in gastric cancer suppression (Qiao et al. 2016).
RUNX3 is a negative regulator of NOTCH signaling and RUNX3-mediated inhibition of NOTCH activity may play a tumor suppressor role in hepatocellular carcinoma (Gao et al. 2010, Nishina et al. 2011).
In addition to RUNX3 silencing through promoter hypermethylation in breast cancer (Lau et al. 2006), Runx3+/- mice are predisposed to breast cancer development. RUNX3 downregulates estrogen receptor alpha (ESR1) protein levels in a proteasome-dependent manner (Huang et al. 2012).
Besides its tumor suppressor role, mainly manifested through its negative effect on cell proliferation, RUNX3 can promote cancer cell invasion by stimulating expression of genes involved in metastasis, such as osteopontin (SPP1) (Whittle et al. 2015).

Literature References
PubMed ID Title Journal Year
16164020 RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters

Domínguez-Soto, A, Relloso, M, Vega, MA, Corbí, AL, Puig-Kröger, A

Immunobiology 2005
15574200 CpG methylation of the FHIT, FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors (GCTs) of ovarian origin

Dhillon, VS, Shahid, M, Husain, SA

Mol. Cancer 2004
24880459 The transcription factor ThPOK suppresses Runx3 and imposes CD4(+) lineage fate by inducing the SOCS suppressors of cytokine signaling

Luckey, MA, Kimura, MY, Waickman, AT, Feigenbaum, L, Singer, A, Park, JH

Nat. Immunol. 2014
18676844 RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking

Wolff, EM, Liang, G, Cortez, CC, Tsai, YC, Castelao, JE, Cortessis, VK, Tsao-Wei, DD, Groshen, S, Jones, PA

Cancer Res. 2008
16804544 CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Weisenberger, DJ, Siegmund, KD, Campan, M, Young, J, Long, TI, Faasse, MA, Kang, GH, Widschwendter, M, Weener, D, Buchanan, D, Koh, H, Simms, L, Barker, M, Leggett, B, Levine, J, Kim, M, French, AJ, Thibodeau, SN, Jass, J, Haile, R, Laird, PW

Nat. Genet. 2006
23334789 Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4⁺ T cell immunity

Reis, BS, Rogoz, A, Costa-Pinto, FA, Taniuchi, I, Mucida, D

Nat. Immunol. 2013
21734270 Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation

Dykes, IM, Tempest, L, Lee, SI, Turner, EE

J. Neurosci. 2011
19800882 RUNX3 directly interacts with intracellular domain of Notch1 and suppresses Notch signaling in hepatocellular carcinoma cells

Gao, J, Chen, Y, Wu, KC, Liu, J, Zhao, YQ, Pan, YL, Du, R, Zheng, GR, Xiong, YM, Xu, HL, Fan, DM

Exp. Cell Res. 2010
11955451 Causal relationship between the loss of RUNX3 expression and gastric cancer

Li, QL, Ito, K, Sakakura, C, Fukamachi, H, Inoue, Ki, Chi, XZ, Lee, KY, Nomura, S, Lee, CW, Han, SB, Kim, HM, Kim, WJ, Yamamoto, H, Yamashita, N, Yano, T, Ikeda, T, Itohara, S, Inazawa, J, Abe, T, Hagiwara, A, Yamagishi, H, Ooe, A, Kaneda, A, Sugimura, T, Ushijima, T, Bae, SC, Ito, Y

Cell 2002
16446142 A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification

Kramer, I, Sigrist, M, de Nooij, JC, Taniuchi, I, Jessell, TM, Arber, S

Neuron 2006
26414766 Runx3 specifies lineage commitment of innate lymphoid cells

Ebihara, T, Song, C, Ryu, SH, Plougastel-Douglas, B, Yang, L, Levanon, D, Groner, Y, Bern, MD, Stappenbeck, TS, Colonna, M, Egawa, T, Yokoyama, WM

Nat. Immunol. 2015
14765120 Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation

Fainaru, O, Woolf, E, Lotem, J, Yarmus, M, Brenner, O, Goldenberg, D, Negreanu, V, Bernstein, Y, Levanon, D, Jung, S, Groner, Y

EMBO J. 2004
21203558 A novel HMM-based method for detecting enriched transcription factor binding sites reveals RUNX3 as a potential target in pancreatic cancer biology

Levkovitz, L, Yosef, N, Gershengorn, MC, Ruppin, E, Sharan, R, Oron, Y

PLoS ONE 2010
16818622 RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer

Lau, QC, Raja, E, Salto-Tellez, M, Liu, Q, Ito, K, Inoue, M, Putti, TC, Loh, M, Ko, TK, Huang, C, Bhalla, KN, Zhu, T, Ito, Y, Sukumar, S

Cancer Res. 2006
20615577 The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expression

Puig-Kröger, A, Aguilera-Montilla, N, Martínez-Nuñez, R, Domínguez-Soto, A, Sánchez-Cabo, F, Martín-Gayo, E, Zaballos, A, Toribio, ML, Groner, Y, Ito, Y, Dopazo, A, Corcuera, MT, Alonso Martín, MJ, Vega, MA, Corbí, AL

Immunobiology 2010
12352981 Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons

Inoue, K, Ozaki, S, Shiga, T, Ito, K, Masuda, T, Okado, N, Iseda, T, Kawaguchi, S, Ogawa, M, Bae, SC, Yamashita, N, Itohara, S, Kudo, N, Ito, Y

Nat. Neurosci. 2002
18184866 Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver

Landry, JR, Kinston, S, Knezevic, K, de Bruijn, MF, Wilson, N, Nottingham, WT, Peitz, M, Edenhofer, F, Pimanda, JE, Ottersbach, K, Göttgens, B

Blood 2008
19446338 The human CD6 gene is transcriptionally regulated by RUNX and Ets transcription factors in T cells

Arman, M, Aguilera-Montilla, N, Mas, V, Puig-Kröger, A, Pignatelli, M, Guigó, R, Corbí, AL, Lozano, F

Mol. Immunol. 2009
21706051 RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α

Huang, B, Qu, Z, Ong, CW, Tsang, YH, Xiao, G, Shapiro, D, Salto-Tellez, M, Ito, K, Ito, Y, Chen, LF

Oncogene 2012
18385258 Dynamic regulation of the expression of neurotrophin receptors by Runx3

Nakamura, S, Senzaki, K, Yoshikawa, M, Nishimura, M, Inoue, K, Ito, Y, Ozaki, S, Shiga, T

Development 2008
26364597 RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancer

Qiao, Y, Lin, SJ, Chen, Y, Voon, DC, Zhu, F, Chuang, LS, Wang, T, Tan, P, Lee, SC, Yeoh, KG, Sudol, M, Ito, Y

Oncogene 2016
26061886 Runx3-regulated expression of two Ntrk3 transcript variants in dorsal root ganglion neurons

Ogihara, Y, Masuda, T, Ozaki, S, Yoshikawa, M, Shiga, T

Dev Neurobiol 2016
15824739 Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

Schulmann, K, Sterian, A, Berki, A, Yin, J, Sato, F, Xu, Y, Olaru, A, Wang, S, Mori, Y, Deacu, E, Hamilton, J, Kan, T, Krasna, MJ, Beer, DG, Pepe, MS, Abraham, JM, Feng, Z, Schmiegel, W, Greenwald, BD, Meltzer, SJ

Oncogene 2005
26004068 RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma

Whittle, MC, Izeradjene, K, Rani, PG, Feng, L, Carlson, MA, DelGiorno, KE, Wood, LD, Goggins, M, Hruban, RH, Chang, AE, Calses, P, Thorsen, SM, Hingorani, SR

Cell 2015
16135801 RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD

Chi, XZ, Yang, JO, Lee, KY, Ito, K, Sakakura, C, Li, QL, Kim, HR, Cha, EJ, Lee, YH, Kaneda, A, Ushijima, T, Kim, WJ, Ito, Y, Bae, SC

Mol. Cell. Biol. 2005
21637926 Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling

Nishina, S, Shiraha, H, Nakanishi, Y, Tanaka, S, Matsubara, M, Takaoka, N, Uemura, M, Horiguchi, S, Kataoka, J, Iwamuro, M, Yagi, T, Yamamoto, K

Oncol. Rep. 2011
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