Abstract 429: The high mobility group A1 oncogene enhances cellular reprogramming to a pluripotent stem-like cell
Authors: Shah Sandeep N. , Kerr Candace , Cope Leslie , Mali Prashant , Zambidis Elias , Lui Cyndi , Hillion Joelle , Belton Amy , Huso David , Resar Linda 
Published: August 2012

The molecular mechanisms that enable cancer cells to metastasize are poorly understood, although emerging evidence indicates that transcriptional networks required for stem cell properties during embryogenesis are co-opted by cancer cells during metastatic progression. To elucidate the molecular underpinnings of “stemness” in cancer and normal development, we investigated transcriptional networks and epigenetic alterations during the induction of pluripotent stem cells. Our focus is the high mobility group A1 (HMGA1) gene, which encodes proteins that bind to AT-rich regions of DNA and orchestrate the assembly of transcription factor complexes to alter chromatin structure and modulate gene expression. Our group first discovered that HMGA1 functions as a potent oncogene in cultured cells and causes aggressive tumors in transgenic mice. Recent studies also identified HMGA1 as a key transcription factor enriched in human embryonic stem (hESCs) cells, induced pluripotent stem cells (iPSCs), refractory leukemia, and high-grade/poorly differentiated cancers arising from diverse tissues. Together, these findings are consistent with the hypothesis that HMGA1 drives an undifferentiated, stem cell-like state during malignant transformation and normal development. To further investigate the role of HMGA1 in the stem cell state, we assessed its function in the derivation of iPSCs using multiple approaches. Here, we demonstrate for the first time that HMGA1 significantly enhances the reprogramming of somatic cells (bone marrow-derived mesenchymal stem cells, fetal lung cells, or mononuclear blood cells) into iPSCs together with OCT4, SOX2, KLF4, and cMYC (OSKM) using a retroviral or episomal, non-integrating approach. When hESCs are induced to differentiate, HMGA1 expression falls and parallels that of other pluripotency factors, such as OCT4, NANOG, and SOX2. We also found that forced expression of HMGA1 blocks differentiation of hESCs. To determine how HMGA1 induces a stem cell state, we assessed gene expression and epigenetic changes. During the reprogramming process, HMGA1 induces the expression of pluripotency and cancer genes, including SOX2, LIN28, and cMYC, while in hESCs, knock-down of HMGA1 results in repression of these genes. In addition, NANOG and OCT4 are repressed in hESCs following knock-down of HMGA1. By chromatin immunoprecipitation, HMGA1 binds to the promoters of SOX2, LIN28, and cMYC in vivo in hESCs. Moreover, HMGA1 is associated with decreased promoter methylation of select stem cell genes early in reprogramming. These findings uncover a key role for HMGA1 as a regulator of the stem cell state through transcriptional networks and epigenetic remodeling that induce pluripotency and an undifferentiated state. Further studies are needed to determine if HMGA1 pathways could be targeted in poorly differentiated, stem-like cancers or exploited in regenerative medicine.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 429. doi:1538-7445.AM2012-429