The high mobility group A1 molecular switch: turning on cancer - can we turn it off?

INTRODUCTION: Emerging evidence demonstrates that the high mobility group A1 (HMGA1) chromatin remodeling protein is a key molecular switch required by cancer cells for tumor progression and a poorly differentiated, stem-like state. Because the HMGA1 gene and proteins are expressed at high levels in all aggressive tumors studied to date, research is needed to determine how to 'turn off' this master regulatory switch in cancer. AREAS COVERED: In this review, we describe prior studies that underscore the central role of HMGA1 in refractory cancers and we discuss approaches to target HMGA1 in cancer therapy. EXPERT OPINION: Given the widespread overexpression of HMGA1 in diverse, aggressive tumors, further research to develop technology to target HMGA1 holds immense promise as potent anticancer therapy. Previous work in preclinical models indicates that delivery of short hairpin RNA or interfering RNA molecules to 'switch off' HMGA1 expression dramatically impairs cancer cell growth and tumor progression. The advent of nanoparticle technology to systemically deliver DNA or RNA molecules to tumors brings this approach even closer to clinical applications, although further efforts are needed to translate these advances into therapies for cancer patients.

High-mobility group A1 (HMGA1) protein expression correlates with cisplatin-induced cell death in squamous cell carcinoma of skin.

It is well known that HMGA1 group of non-histone chromosomal proteins are up-regulated in several human cancers. We studied the HMGA1 expression in squamous cell carcinoma of skin in mice followed by the treatment with Cisplatin, which is often used in combination therapies of cancers. A short course of Cisplatin treatment led to apoptotic cell death and downregulation (by 40%) of HMGA1. However, extended treatment of Cisplatin caused necrotic cell death; concomitantly HMGA1 expression decreased by 90%. Present results indicate a strong association of HMGA1 with Cisplatin-linked tumor regression. Therefore, HMGA1 could be a potential target in designing therapeutic strategies against cancer.

Regulation of microRNA expression by HMGA1 proteins.

The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

The HMGA proteins: a myriad of functions (Review).

The 'high mobility group' HMGA protein family consists of four members: HMGA1a, HMGA1b and HMGA1c, which result from translation of alternative spliced forms of one gene and HMGA2, which is encoded for by another gene. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing the DNA conformation by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. In this way, they influence a diverse array of normal biological processes including cell growth, proliferation, differentiation and death. Both HMGA1 and HMGA2 are hardly detectable in normal adult tissue but are abundantly and ubiquitously expressed during embryonic development. In malignant epithelial tumors as well as in leukemia, however, expression of HMGA1 is again strongly elevated to embryonic levels thus leading to ectopic expression of (fetal) target genes. HMGA2 overexpression also has a causal role in inducing neoplasia. Besides overexpression of full length HMGA proteins in different tumors, the HMGA genes are often involved in chromosomal rearrangements. Such translocations are mostly detected in benign tumors of mesenchymal origin and are believed to be one of the most common chromosomal rearrangements in human neoplasia. To provide clarity in the abundance of articles on this topic, this review gives a general overview of the nuclear functions and regulation of the HMGA genes and corresponding proteins.

Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation.

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.