Abstract 3352: HMGA1 chromatin remodeling protein induces HOXB13 to drive cancer stem cell properties and tumor progression in prostate cancer models

Abstract

Abstract Increasing evidence suggests that cancer cells undergo chromatin remodeling and epigenetic reprogramming during tumor progression, although the underlying mechanisms remain poorly understood. The High Mobility Group A1 (HMGA1) chromatin binding protein is an architectural transcription factor that binds to AT-rich regions in DNA where it displaces histone HI and recruits transcriptional complexes to modulate gene expression. The HMGA1 gene is highly expressed during embryogenesis and in adult stem cells, but silenced postnatally in differentiated tissues. HMGA1 becomes re-expressed in most high-grade cancers and high levels portend adverse clinical outcomes. In prostate cancer (PCa), HMGA1 overexpression and protein immunoreactivity associates with high pathologic grade, although its function in this setting is unknown. To gain mechanistic into the role of HMGA1 in PCa, we silenced HMGA1 in 2 human PCa cell lines: 1) PC3-Epi, a PCa clone selected for epithelial properties, and 2) PC3-EMT, a more invasive PCa clone with mesenchymal properties. Silencing HMGA1 halts proliferation in both PC3-Epi and PC3-EMT cells. Cell morphology changed most dramatically in the PC3-EMT cells, transforming spindle-shaped, mesenchymal cells to more cuboidal, epithelial-like cells. Both migration and invasion were disrupted, but only in the more invasive PC-EMT cells. Colony formation and the stem cell property, three-dimensional (3D) sphere formation, were also blocked in cells with HMGA1 knock-down. To elucidate transcriptional networks downstream of HMGA1, RNA-seq was performed in both cell lines + HMGA1 silencing. We identified genes involved in cell signaling, protein synthesis, post-translational modifications, cell motility, mitotic spindle formation, and development. We focused on the HOXB13 developmental gene, which encodes a transcription factor involved in prostate development. Intriguingly, HOXB13 germline mutations are linked to familial PCa. We found that HOXB13 and HMGA1 are co-regulated in PCa cells by quantitative RT-PCR. HMGA1 occupies 2 sites within the HOXB13 promoter region by chromatin immunoprecipitation. Strikingly, silencing HOXB13 recapitulates HMGA1 phenotypes, impairing proliferation, colony formation, and 3D sphere formation. This work not only reveals a novel role for HMGA1 in regulating both cancer stem cell properties and tumor progression in PCa through HOXB13, but also suggests that targeting the HMGA1-HOXB13 pathway could be effective therapy in invasive PCa. Citation Format: Lionel Chia, Lingling Xian, Guangjing Zhu, Mohammad Heydarian, William B. Issacs, Karen Reddy, Linda Smith Resar. HMGA1 chromatin remodeling protein induces HOXB13 to drive cancer stem cell properties and tumor progression in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3352.