SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration.
SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration.
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上皮-间质转化 (EMT) 是一种可逆的细胞程序，可将上皮 (E) 细胞暂时置于假间质 (M) 细胞状态。许多癌症的恶性进展和抵抗取决于肿瘤细胞中的 EMT 激活、部分 EMT 或混合 E/M 状态。 EMT 由肿瘤微环境 TGFβ 信号和肿瘤细胞中 EMT 诱导转录因子（例如 ZEB1/2）激活。然而，反向EMT因素的研究较少。我们证明，前列腺上皮转录因子 SCAND1 可以将癌细胞间质和混合 E/M 表型逆转为上皮性更强、侵袭性更小的状态，并抑制其在 DU-145 前列腺癌细胞中的增殖和迁移。 SCAND1 是一种包含 SCAN 结构域的蛋白质，与 SCAN 锌指转录因子（例如 MZF1）异源寡聚化，用于访问 DNA 和靶基因的转录共抑制。我们发现 SCAND1 表达与维持上皮特征相关，而 SCAND1 缺失与肿瘤细胞的间充质表型相关。 SCAND1和MZF1可相互诱导并与异染色质蛋白HP1γ协同包含在染色质中。 SCAND1 的过度表达将杂合 E/M 状态逆转为具有 E-钙粘蛋白和 β-连环蛋白重新定位的上皮表型。 TCGA PanCancer Atlas 中的共表达分析一致表明，前列腺腺癌标本中 SCAND1 和 MZF1 表达与 EMT 驱动基因（包括 CTNNB1、ZEB1、ZEB2 和 TGFBR）呈负相关。此外，SCAND1 过表达通过减少 MAP3K-MEK-ERK 信号通路抑制肿瘤细胞增殖。值得注意的是，在小鼠肿瘤异种移植模型中，SCAND1过表达显着减少Ki-67(+)和Vimentin(+)肿瘤细胞，并抑制前列腺癌的迁移和淋巴结转移。 Kaplan-Meier 分析显示 SCAND1 和 MZF1 的高表达与胰腺癌和头颈癌的较好预后相关，但肾癌的预后较差。总体而言，这些数据表明 SCAND1 诱导 MZF1 的表达并协调异染色质结合，将混合 E/M 状态逆转为上皮表型，并可能通过抑制 EMT 驱动基因表达和 MAP3K-MEK-ERK 信号通路来抑制肿瘤细胞增殖、迁移和转移。
Epithelial–mesenchymal transition (EMT) is a reversible cellular program that transiently places epithelial (E) cells into pseudo-mesenchymal (M) cell states. The malignant progression and resistance of many carcinomas depend on EMT activation, partial EMT, or hybrid E/M status in neoplastic cells. EMT is activated by tumor microenvironmental TGFβ signal and EMT-inducing transcription factors, such as ZEB1/2, in tumor cells. However, reverse EMT factors are less studied. We demonstrate that prostate epithelial transcription factor SCAND1 can reverse the cancer cell mesenchymal and hybrid E/M phenotypes to a more epithelial, less invasive status and inhibit their proliferation and migration in DU-145 prostate cancer cells. SCAND1 is a SCAN domain-containing protein and hetero-oligomerizes with SCAN-zinc finger transcription factors, such as MZF1, for accessing DNA and the transcriptional co-repression of target genes. We found that SCAND1 expression correlated with maintaining epithelial features, whereas the loss of SCAND1 was associated with mesenchymal phenotypes of tumor cells. SCAND1 and MZF1 were mutually inducible and coordinately included in chromatin with hetero-chromatin protein HP1γ. The overexpression of SCAND1 reversed hybrid E/M status into an epithelial phenotype with E-cadherin and β-catenin relocation. Consistently, the co-expression analysis in TCGA PanCancer Atlas revealed that SCAND1 and MZF1 expression was negatively correlated with EMT driver genes, including CTNNB1, ZEB1, ZEB2 and TGFBRs, in prostate adenocarcinoma specimens. In addition, SCAND1 overexpression suppressed tumor cell proliferation by reducing the MAP3K-MEK-ERK signaling pathway. Of note, in a mouse tumor xenograft model, SCAND1 overexpression significantly reduced Ki-67(+) and Vimentin(+) tumor cells and inhibited migration and lymph node metastasis of prostate cancer. Kaplan–Meier analysis showed high expression of SCAND1 and MZF1 to correlate with better prognoses in pancreatic cancer and head and neck cancers, although with poorer prognosis in kidney cancer. Overall, these data suggest that SCAND1 induces expression and coordinated heterochromatin-binding of MZF1 to reverse the hybrid E/M status into an epithelial phenotype and, inhibits tumor cell proliferation, migration, and metastasis, potentially by repressing the gene expression of EMT drivers and the MAP3K-MEK-ERK signaling pathway.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3.7
作者：
Eguchi T;Watanabe K;Hara ES;Ono M;Kuboki T;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
4
作者：
Eguchi T;Prince T;Wegiel B;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
3.7
作者：
Eguchi T;Sogawa C;Okusha Y;Uchibe K;Iinuma R;Ono K;Nakano K;Murakami J;Itoh M;Arai K;Fujiwara T;Namba Y;Murata Y;Ohyama K;Shimomura M;Okamura H;Takigawa M;Nakatsura T;Kozaki KI;Okamoto K;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
0.7
作者：
Angela Nieto, M.
通讯作者：
Angela Nieto, M.