Ogata Takehiro, Nakamura Mizuyo, Sang Meijie, Yoda Hiroyuki, Hiraoka Kiriko, Yin Danjing, Sang Mexiang, Shimozato Osamu, Ozaki Toshinori
Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan.
Department of Regenerative Medicine, Graduate School of Medicine, University of Toyama, Toyama, Japan.
PLoS One. 2017 Jul 3;12(7):e0179884. doi: 10.1371/journal.pone.0179884. eCollection 2017.
Suberoylanilide hydroxamic acid (SAHA) represents one of the new class of anti-cancer drugs. However, multiple lines of clinical evidence indicate that SAHA might be sometimes ineffective on certain solid tumors including pancreatic cancer. In this study, we have found for the first time that RUNX2/mutant p53/TAp63-regulatory axis has a pivotal role in the determination of SAHA sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells. According to our present results, MiaPaCa-2 cells responded poorly to SAHA. Forced depletion of mutant p53 stimulated SAHA-mediated cell death of MiaPaCa-2 cells, which was accomapanied by a further accumulation of γH2AX and cleaved PARP. Under these experimental conditions, pro-oncogenic RUNX2 was strongly down-regulated in mutant p53-depleted MiaPaCa-2 cells. Surprisingly, RUNX2 silencing augmented SAHA-dependent cell death of MiaPaCa-2 cells and caused a significant reduction of mutant p53. Consistent with these observations, overexpression of RUNX2 in MiaPaCa-2 cells restored SAHA-mediated decrease in cell viability and increased the amount of mutant p53. Thus, it is suggestive that there exists a positive auto-regulatory loop between RUNX2 and mutant p53, which might amplify their pro-oncogenic signals. Intriguingly, knockdown of mutant p53 or RUNX2 potentiated SAHA-induced up-regulation of TAp63. Indeed, SAHA-stimulated cell death of MiaPaCa-2 cells was partially attenuated by p63 depletion. Collectively, our present observations strongly suggest that RUNX2/mutant p53/TAp63-regulatory axis is one of the key determinants of SAHA sensitivity of p53-mutated pancreatic cancer cells.
伏立诺他（SAHA）是新型抗癌药物之一。然而，多项临床证据表明，SAHA有时对包括胰腺癌在内的某些实体瘤无效。在本研究中，我们首次发现RUNX2/突变型p53/TAp63调控轴在决定p53突变的胰腺癌MiaPaCa-2细胞对SAHA的敏感性中起关键作用。根据我们目前的结果，MiaPaCa-2细胞对SAHA反应不佳。强制去除突变型p53可刺激SAHA介导的MiaPaCa-2细胞死亡，同时伴随着γH2AX和裂解的PARP进一步积累。在这些实验条件下，促癌基因RUNX2在去除突变型p53的MiaPaCa-2细胞中强烈下调。令人惊讶的是，RUNX2沉默增强了SAHA依赖型MiaPaCa-2细胞死亡，并导致突变型p53显著减少。与这些观察结果一致，在MiaPaCa-2细胞中过表达RUNX2可恢复SAHA介导的细胞活力下降，并增加突变型p53的量。因此，提示RUNX2与突变型p53之间存在正性自调节环，这可能会放大它们的促癌信号。有趣的是，敲低突变型p53或RUNX2可增强SAHA诱导的TAp63上调。事实上，p63缺失可部分减弱SAHA刺激的MiaPaCa-2细胞死亡。总的来说，我们目前的观察结果强烈表明，RUNX2/突变型p53/TAp63调控轴是p53突变的胰腺癌细胞对SAHA敏感性的关键决定因素之一。
BMC Cancer. 2018-3-20
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