Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer

Abstract

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.

Triple Fluorescence staining to Evaluate Mechanism-based Apoptosis following Chemotherapeutic and Targeted Anti-cancer Drugs in Live Tumor Cells

“…We performed immunoblots by Western blots on the equivalent amounts of protein (Bradford assay) using clarified cell lysates as mentioned earlier 11 . Normalized lysates (20–40 μg protein) were resolved by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis for Western blot 10 .…”

Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts

“…Taken together, it is possible that these findings constitute an integrated axis of IFN-controlled maintenance of CSCs through sumoylation. As such, therapeutic targeting of sumoylation could be key to eradicating resident CSCs [181,[185][186][187]. Inhibition of the SUMO pathway can also restore chemosensitivity in chemotherapy-resistant acute myeloid leukemia (AML) [188], or sensitize non-APL AMLs to retinoid-induced differentiation therapy [189].…”

Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma

“…The hub gene TYMS is also involved in one carbon pool by folate pathway; FOS, JUN, and CDH1 genes are involved in pathways in cancer; and JUN and FOS genes are involved in the oestrogen signalling pathway. A number of other hub genes have been described as associated with malignant thyroid cancers, including EXH2, UBCH10,TFAP2A, TOP2A, and SRF [50][51][52][53][54]. By considering the possible roles of these hub proteins in pathogenesis of FTC and other related diseases, new roles for these proteins may be identified.…”