Abstract 2595: HMGA1 induces the HOXB13 developmental gene to drive tumor progression in androgen receptor negative, castrate-resistant prostate cancer
Authors: Chia Lionel , Zhu Guangjing , Gorbounov Mikhail , Xian Lingling , Chisholm Briyana , Heydarian Mohammad , Johng Dorhyun , Isaacs William B. , Reddy Karen , Resar Linda S. 
Published: August 2019

Abstract
While High Mobility Group A1 (HMGA1) chromatin remodeling proteins are frequently dysregulated in diverse cancers, their molecular underpinnings in carcinogenesis remain poorly understood. HMGA1 are small, non-histone proteins that bind to AT-rich regions in DNA, bend chromatin, and recruit transcriptional complexes to modulate gene expression. Prior studies in prostate cancer (PCa) suggest that HMGA1 overexpression associates with higher pathologic grades and increases in HMGA1 protein levels correlate with metastatic potential in rat PCa cells. Overexpression of HMGA1 in human PCa cell lines induces unbalanced chromosomal rearrangements in vitro. Thus, we hypothesized that HMGA1 drives PCa progression through epigenetic reprogramming of transcriptional networks involved in development and chromosomal instability. To test this, we focused on androgen receptor (AR)-negative, castrate-resistant PCa (CRPC) cell lines as tumors with these features are resistant to therapy and associated with metastatic progression and early death. Here, we uncover a novel role for HMGA1 in regulating HOXB13 to drive tumor progression and cancer stem cell properties. We found that silencing HMGA1 in patient-derived metastatic cell lines (PC3-Epi, PC3-EMT, DU145) halts proliferation. Cell morphology changed most dramatically in PC3-EMT cells, transforming spindle-shaped, mesenchymal cells to more cuboidal, epithelial-like cells. Both migration and invasion were disrupted, but primarily in more invasive, mesenchymal cell lines (PC-EMT, DU145). Colony formation and 3D sphere formation were also blocked in all CRPC lines. Immunohistologic analysis in primary tumors revealed that HMGA1 nuclear staining associates with more advanced Gleason scores in PCa. To elucidate transcriptional networks downstream of HMGA1, RNA-seq was performed in PC3-EMT and PC3-Epi cell lines + HMGA1 silencing. Intriguingly, HMGA1 regulates pathways involved in inflammation in the more epithelial PC3-Epi cells, while pathways involved in mitosis, cell cycle progression, DNA damage, and checkpoint regulation predominated in the mesenchymal PC3-EMT cells. Pathways involved in proliferation and development were regulated by HMGA1 in both settings. We focused on HOXB13, a developmental gene linked to cell fate and prostate carcinogenesis. Both HOXB13 and HMGA1 are co-regulated in CRPC cell lines at the gene expression and protein level. HMGA1 occupies at least 1 site within the HOXB13 promoter region by chromatin immunoprecipitation. Strikingly, silencing HOXB13recapitulates HMGA1 phenotypes, impairing proliferation, colony formation, and 3D sphere formation. These findings reveal a novel role for HMGA1 in CRPC progression by dysregulating developmental networks. Together, these results also suggest that targeting the HMGA1-HOXB13 pathway could be effective therapy in CRPC.
Citation Format: Lionel Chia, Guangjing Zhu, Mikhail Gorbounov, Lingling Xian, Briyana Chisholm, Mohammad Heydarian, Dorhyun Johng, William B. Isaacs, Karen Reddy, Linda S. Resar. HMGA1 induces the HOXB13 developmental gene to drive tumor progression in androgen receptor negative, castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2595.