Mechanistic Role of High Mobility Group A2 (Hmga2) Truncated Isoform in Prostate Cancer Progression
Campbell, Taaliah, Clark Atlanta University
2023-05
2020-2029
Given the complexity and propensity of prostate cancer (PCa) to metastasize to bone, advanced PCa continues to be one of the more challenging malignancies to comprehend. Oxidative stress, a key feature of cancer, is found to be increased in a number of cancers including PCa and is being used as a means of inducing ferroptosis, an unusual type of cell death, as part of cancer treatment. The non-histone protein HMGA2, which is overexpressed in a variety of cancers, can be shortened due to chromosomal rearrangement or alternative splicing of the HMGA2 gene. HMGA2 is known to play a fundamental role in metastasis to bone and cancer progression in several cancers, however, very little is known about its mechanism in PCa progression. The purpose of this study is to investigate the role of wild-type vs. truncated HMGA2 in PCa progression and bone metastasis. The study analyzed the expression of wild-type and truncated HMGA2 in prostate cancer patients and cell lines, finding that both forms were expressed more in higher tumor grades and metastasis compared to normal cells. We then focused on the effects of the two forms on oxidative stress and ferroptosis, finding that truncated HMGA2 increases oxidative stress and sensitivity to ferroptosis compared to wild-type HMGA2 or control cells. Furthermore, cytoplasmic HMGA2 interacts with G3BP1, a protein that responds to oxidative stress, and silencing G3BP1 increases sensitivity to ferroptosis. Knocking down either HMGA2 or G3BP1 increases ferroptosis, which could be reversed by a ferroptosis inhibitor. Furthermore, RISH staining displays both isoforms present in bone metastatic tissue. LNCaP PCa cell lines stably overexpressing either full length or truncated HMGA2 co-cultured with bone components hydroxyapatite and ground bone matrix also was shown to lead to paracrine increases in cell migration and proliferation, which can be abrogated by MAPK inhibition. Overall, we have uncovered novel roles for HMGA2, particularly truncated HMGA2, in promoting oxidative stress which makes it more susceptible to ferroptosis, while at the bone metastatic site, HMGA2 differentially contributes to PCa/bone interactions that may drive bone metastasis.
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Atlanta University and Clark Atlanta University Theses and Dissertations
dissertation
Doctor of Philosophy (PhD)
Clark Atlanta University
Department of Biological Sciences
Hinton, Cimona
Georgia--Atlanta
http://hdl.handle.net/20.500.12322/cau.td:2023_campbell_taaliah
http://rightsstatements.org/vocab/InC-EDU/1.0/
