jeffrey-r-white@uiowa.edu
Mentor: Ronald Weigel, M.D./Ph.D./MBA
Lab Room: 5269 CBRB
Lab Phone: 319-335-6828

Examining the Influence of TFAP2A Sumoylation in Melanoma

Transcription Factor AP-2 Alpha (TFAP2A) is a developmentally critical transcription factor regulating the differentiation of neural crest cells. Dysregulation of TFAP2A has been shown to drive the progression of multiple types of cancer including breast, colorectal, anaplastic thyroid, and melanoma. Previous work in the Weigel Lab has demonstrated functional modulation of TFAP2A through its post-translational modification by Small Ubiquitin-like Modifier proteins (SUMO proteins), altering the transcriptional activities of TFAP2A. This post-translational modification prevents TFAP2A-mediated repression of CD44 and MMP14, genes driving metastatic progression. While we have shown inhibiting sumoylation of TFAP2A halts invasiveness of a subset of carcinomas, its role in melanoma remains unclear. My research project involves investigating the transcriptional contribution of TFAP2A sumoylation to melanoma progression.

Bogachek MV, Park JM, De Andrade JP, Lorenzen AW, Kulak MV, White JR, Gu VW, Wu VT, Weigel RJ. Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas. Stem Cell Reports. 2016 Dec 13;7(6):1140-1151. doi: 10.1016/j.stemcr.2016.11.001. Epub 2016 Dec 1. PubMed PMID: 27916539; PubMed Central PMCID: PMC5161532.

Bogachek MV, Park JM, De Andrade JP, Kulak MV, White JR, Wu T, Spanheimer PM, Bair TB, Olivier AK, Weigel RJ. A novel animal model for locally advanced breast cancer. Ann Surg Oncol. 2015 Mar;22(3):866-73. doi: 10.1245/s10434-014-4174-8. Epub 2014 Oct 18. PubMed PMID: 25326397; PubMed Central PMCID: PMC4425290.

Bogachek M.V., Park J.M., De Andrade J. P., Kulak M.V., White J.R., Wu T., Spanheimer P.M., Woodfield G.W., Bair T.B., Olivier A.K., Weigel R.J. SUMO Inhibitors affect tumorigenesis of novel breast cancer xenograft model [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-02-03.

Melanoma prognoses dramatically worsen following metastasis. Determining metastatic drivers supports using novel drugs targeting this grim progression. We uncovered a regulatory network where transcription factor AP-2alpha supports melanoma metastasis by activating interrelated pro-survival genes. This culminates in AP-2alpha-mediated upregulation of EZH2, a pro-metastatic histone methyltransferase. A highly specific EZH2 inhibitor halts metastatic behaviors of melanoma cells and elicits a heritable abolishment of metastasis in vivo, supporting its efficacy as an anti-metastatic therapy for advanced melanoma.

Franke CM, Gu VW, Grimm BG, Cassady VC, White JR, Weigel RJ, Kulak MV. TFAP2C regulates carbonic anhydrase XII in human breast cancer. Oncogene 39, 1290–1301 (2020). https://doi.org/10.1038/s41388-019-1062-5