HOXB13 通过超级增强子控制细胞状态。

HOXB13 controls cell state through super-enhancers.

机构信息

Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.

出版信息

Exp Cell Res. 2020 Aug 1;393(1):112039. doi: 10.1016/j.yexcr.2020.112039. Epub 2020 May 4.

DOI:10.1016/j.yexcr.2020.112039

PMID:32376288

Abstract

Expression of the homeodomain transcription factor HOXB13 has been demonstrated in several malignancies but its role in tumorigenesis remains elusive. We observed high levels of HOXB13 in poorly differentiated pediatric tumors including a highly aggressive childhood neoplasm - malignant rhabdoid tumor. In a xenograft model of rhabdoid tumor, knockout of HOXB13 diminished tumor growth while partial knockdown of HOXB13 promoted differentiation of tumor cells into bone. These results suggest that HOXB13 enhances rhabdoid malignancy by interfering with mesenchymal stem cell differentiation. Consistent with this hypothesis, overexpression of HOXB13 in mesenchymal progenitor cells inhibited adipogenic, myogenic, and osteogenic differentiation. Mechanistically, we demonstrated that HOXB13 binds to super-enhancer regions regulating genes involved in differentiation and tumorigenesis.

摘要

同源盒转录因子 HOXB13 的表达已在多种恶性肿瘤中得到证实，但它在肿瘤发生中的作用仍不清楚。我们观察到 HOXB13 在分化不良的儿科肿瘤中高水平表达，包括一种高度侵袭性的儿童肿瘤——恶性横纹肌样瘤。在横纹肌样瘤的异种移植模型中，HOXB13 的敲除减少了肿瘤的生长，而 HOXB13 的部分敲低促进了肿瘤细胞向骨的分化。这些结果表明，HOXB13 通过干扰间充质干细胞分化来增强横纹肌样瘤的恶性程度。与这一假说一致的是，HOXB13 在间充质祖细胞中的过表达抑制了脂肪生成、成肌和成骨分化。在机制上，我们证明 HOXB13 结合到调节分化和肿瘤发生相关基因的超级增强子区域。