Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.
Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt.
Int J Mol Sci. 2023 Mar 8;24(6):5168. doi: 10.3390/ijms24065168.
The cell stress response is an essential system present in every cell for responding and adapting to environmental stimulations. A major program for stress response is the heat shock factor (HSF)-heat shock protein (HSP) system that maintains proteostasis in cells and promotes cancer progression. However, less is known about how the cell stress response is regulated by alternative transcription factors. Here, we show that the SCAN domain (SCAND)-containing transcription factors (SCAN-TFs) are involved in repressing the stress response in cancer. SCAND1 and SCAND2 are SCAND-only proteins that can hetero-oligomerize with SCAN-zinc finger transcription factors, such as MZF1(ZSCAN6), for accessing DNA and transcriptionally co-repressing target genes. We found that heat stress induced the expression of SCAND1, SCAND2, and MZF1 bound to gene promoter regions in prostate cancer cells. Moreover, heat stress switched the transcript variants' expression from long noncoding RNA (lncRNA-SCAND2P) to protein-coding mRNA of SCAND2, potentially by regulating alternative splicing. High expression of correlated with poorer prognoses in several cancer types, although SCAND1 and MZF1 blocked the heat shock responsiveness of in prostate cancer cells. Consistent with this, gene expression of , , and was negatively correlated with gene expression in prostate adenocarcinoma. By searching databases of patient-derived tumor samples, we found that MZF1 and SCAND2 RNA were more highly expressed in normal tissues than in tumor tissues in several cancer types. Of note, high RNA expression of SCAND2, SCAND1, and MZF1 correlated with enhanced prognoses of pancreatic cancer and head and neck cancers. Additionally, high expression of SCAND2 RNA was correlated with better prognoses of lung adenocarcinoma and sarcoma. These data suggest that the stress-inducible SCAN-TFs can function as a feedback system, suppressing excessive stress response and inhibiting cancers.
细胞应激反应是每个细胞中存在的一种重要系统，用于对外界刺激做出反应和适应。应激反应的一个主要程序是热休克因子 (HSF)-热休克蛋白 (HSP) 系统，该系统可维持细胞内的蛋白质平衡并促进癌症进展。然而，人们对细胞应激反应如何被替代转录因子调控知之甚少。在这里，我们表明 SCAN 结构域 (SCAND) 包含的转录因子 (SCAN-TFs) 参与抑制癌症中的应激反应。SCAND1 和 SCAND2 是仅含有 SCAND 的蛋白质，可与 SCAN-锌指转录因子（如 MZF1(ZSCAN6)）形成异源寡聚体，从而访问 DNA 并转录共抑制靶基因。我们发现热应激诱导了前列腺癌细胞中基因启动子区域的 SCAND1、SCAND2 和 MZF1 的表达。此外，热应激将转录变体的表达从长非编码 RNA (lncRNA-SCAND2P) 转换为 SCAND2 的蛋白质编码 mRNA，这可能是通过调节可变剪接实现的。在几种癌症类型中，的高表达与预后较差相关，尽管 SCAND1 和 MZF1 阻断了前列腺癌细胞中热休克对的反应性。与此一致的是，前列腺腺癌中基因表达与基因表达呈负相关。通过搜索患者衍生的肿瘤样本数据库，我们发现 MZF1 和 SCAND2 RNA 在几种癌症类型的正常组织中的表达高于肿瘤组织。值得注意的是，SCAND2、SCAND1 和 MZF1 的 RNA 高表达与胰腺癌和头颈部癌症的预后改善相关。此外，SCAND2 RNA 的高表达与肺腺癌和肉瘤的预后改善相关。这些数据表明，应激诱导的 SCAN-TFs 可以作为一个反馈系统，抑制过度的应激反应并抑制癌症。
