Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer
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James P. De Andrade1,*, Allison W. Lorenzen1,*, Vincent T. Wu1, Maria V. Bogachek1, Jung M. Park1,2, Vivian W. Gu1,3, Claire M. Sevenich1, Victoria C. Cassady1, Anna C. Beck1, Mikhail V. Kulak1, Robert A. Robinson4, Geeta Lal1 and Ronald J. Weigel1,2,3
1Department of Surgery, University of Iowa, Iowa City, IA, USA
2Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
3Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
4Department of Pathology, University of Iowa, Iowa City, IA, USA
*These authors contributed equally to the work and are co-first authors
Ronald J. Weigel, email: [email protected]
Keywords: SUMO; sumoylation; TFAP2A; anaplastic thyroid cancer
Received: March 07, 2017 Accepted: September 15, 2017 Published: October 23, 2017
Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway repressed CD44 and cleared the CSC population, mediated through SUMO-unconjugated TFAP2A. We sought to evaluate effects of inhibiting the SUMO pathway in ATC. ATC cell lines and primary ATC tumor samples were evaluated. The SUMO pathway was inhibited by knockdown of PIAS1 and use of SUMO inhibitors anacardic acid and PYR-41. The expression of TFAP2A in primary ATC was examined by immunohistochemistry. All ATC cell lines expressed TFAP2A but only 8505C expressed SUMO-conjugated TFAP2A. In 8505C only, inhibition of the SUMO pathway by knockdown of PIAS1 or treatment with SUMO inhibitors repressed expression of CD44 with a concomitant loss of SUMO-conjugated TFAP2A. The effect of SUMO inhibition on CD44 expression was dependent upon TFAP2A. Treatment with SUMO inhibitors resulted in a statistically improved tumor-free survival in mice harboring 8505C xenografts. An examination of primary ATC tissue determined that TFAP2A was expressed in 4 of 11 tumors surveyed. We conclude that inhibition of the SUMO pathway repressed the CSC population, delaying the outgrowth of tumor xenografts in ATC. The effect of SUMO inhibition was dependent upon expression of SUMO-conjugated TFAP2A, which may serve as a molecular marker for therapeutic effects of SUMO inhibitors. The findings provide pre-clinical evidence for development of SUMO inhibitors for the treatment of ATC.
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