Role of High Mobility Group A2 (HMGA2) in Prostate Cancer

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Project Summary Black men which includes African American men (AA), Caribbean and African men suffer disproportionately from prostate cancer and have higher mortality rates as compared to Caucasian men (CA), presenting with more aggressive disease at the time of diagnosis. Most men who die of prostate cancer present with hormone refractory and bone metastatic disease. High mobility group protein A2 (HMGA2) belongs to the high mobility chromosomal proteins that rearrange chromatin and is increased in various cancers. A truncated isoform of HMGA2 can also be generated by chromosomal rearrangements or alternative splicing. Additionally, HMGA2 single nucleotide polymorphism (SNP) rs1042725 has been associated with variation in bone mineral density, where the ‘CC’ genotype (more common in Black men vs CA) is associated with higher bone density as compared to ‘TT’ genotype that is more common in CA. Previously it has been shown that increased bone density is associated with prostate cancer incidence in older men from Trinidad and Tobago, and it is well known that Black men have higher bone density than any other race; however it has not been studied with regards to prostate cancer metastasis. Moreover, HMGA2 SNP rs1042725 has been associated with the incidence of cervical cancer, but has not been studied with respect to prostate cancer. We have preliminary data that HMGA2 expression increases with prostate cancer progression and metastasis in patient tissue. Additionally, we found that overexpression of full-length (wild-type) HMGA2 in LNCaP cells promoted nuclear expression of HMGA2 and epithelial mesenchymal transition (EMT), while truncated HMGA2 overexpression led to cytoplasmic localization of HMGA2, increased cell migration via increased Jun-D and reactive oxygen species (ROS). Finally, culturing less aggressive LNCaP cells with conditioned media from a co-culture of metastatic C4-2 cancer cells with hydroxyapatite bone increased HMGA2 expression and paracrine cell migration in vitro, while in vivo, more cancer cells migrated towards hydroxyapatite implant of higher bone density. We hypothesize that HMGA2 isoforms can differentially mediate prostate cancer progression, and that HMGA2 SNPs will be associated with higher prostate cancer incidence in Black men. Firstly, we will examine the expression of HMGA2, both wild-type and truncated in clinical samples of patients from different races, and the mechanism of action of wild-type vs truncated HMGA2 (Specific Aim 1). Secondly, we will examine the correlation between HMGA2 SNPs with prostate cancer incidence (Specific Aim 2). Thirdly, we will determine the molecular mechanisms by which HMGA2 may mediate prostate cancer interactions with bone using in vitro and in vivo mouse models (Specific Aim 3). These studies will reveal a novel functional role for HMGA2 in prostate health disparities.