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Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Tumor Cell Cycle Progression

ABSTRACT: The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Román González-Prieto

LAB HEAD: Alfred C.O. Vertegaal

PROVIDER: PXD024521 | Pride | 2022-01-10

REPOSITORIES: Pride

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Project description:Post translational protein modifications (PTMs) including small chemical groups and small proteins, belonging to the ubiquitin family, are essential for virtually all cellular processes. In addition to modification by a single PTM, proteins can be modified by a combination of different modifiers, which are able to influence each other. Since little is known about crosstalk between different ubiquitin family members, we developed an improved method enabling identification of co-modified proteins on a system-wide level using mass spectrometry. We focused on the role of crosstalk between SUMO and ubiquitin during proteasomal degradation. Using two complementary approaches, we identified 498 proteins to be significantly co-modified by SUMO and ubiquitin upon MG132 treatment. These targets included many enzymatic components of PTM machinery, involved in SUMOylation and ubiquitylation, but also phosphorylation, methylation and acetylation, revealing a highly complex interconnected network of crosstalk between different PTMs. In addition various other biological processes were found to be significantly enriched within the group of co-modified proteins, including transcription, DNA repair and the cell cycle. Interestingly, the latter group mostly consisted of proteins involved in mitosis, including a subset of chromosome segregation regulators. We hypothesize that group modification by SUMO-targeted ubiquitin ligases regulates the stability of the identified subset of mitotic proteins, which ensures proper chromosome segregation. The mitotic regulators KIF23 and MIS18BP1 were verified to be co-modified by SUMO and ubiquitin upon inhibition of the proteasome and subsequently identified as novel RNF4 targets. Both modifications on MIS18BP1 were observed to increase simultaneously during late mitosis, while the total protein level decreased immediately afterwards. These results confirm the regulation of MIS18BP1 via SUMO-ubiquitin crosstalk during mitosis. Combined, our work highlights extensive crosstalk between SUMO and ubiquitin, providing a resource for further unraveling of SUMO-ubiquitin crosstalk.

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	q105936a.raw	Raw

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Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Tumor Cell Cycle Progression

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