Abstract
In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
| Original language | English |
|---|---|
| Pages (from-to) | 1787-1799 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 73 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor hif-1α in a P53-independent manner. / Wu, Shourong; Kasim, Vivi; Kano, Mitsunobu; Tanaka, Sayaka; Ohba, Shinsuke; Miura, Yutaka; Miyata, Kanjiro; Liu, Xueying; Ako Matsuhashi, Matsuhashi; Chung, Ung Il; Yang, Li; Kataoka, Kazunori; Nishiyama, Nobuhiro; Miyagishi, Makoto.
In: Cancer Research, Vol. 73, No. 6, 15.03.2013, p. 1787-1799.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor hif-1α in a P53-independent manner
AU - Wu, Shourong
AU - Kasim, Vivi
AU - Kano, Mitsunobu
AU - Tanaka, Sayaka
AU - Ohba, Shinsuke
AU - Miura, Yutaka
AU - Miyata, Kanjiro
AU - Liu, Xueying
AU - Ako Matsuhashi, Matsuhashi
AU - Chung, Ung Il
AU - Yang, Li
AU - Kataoka, Kazunori
AU - Nishiyama, Nobuhiro
AU - Miyagishi, Makoto
PY - 2013/3/15
Y1 - 2013/3/15
N2 - In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
AB - In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
UR - http://www.scopus.com/inward/record.url?scp=84875473756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875473756&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-0366
DO - 10.1158/0008-5472.CAN-12-0366
M3 - Article
C2 - 23328582
AN - SCOPUS:84875473756
VL - 73
SP - 1787
EP - 1799
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -