SUMOylation in Lymphoma: Mechanisms and Therapeutic Targeting of the SENP6-RNF4 Axis

• Applicants: Professor Dr. Ulrich Keller; Professor Dr. Stefan Müller
• Subject Area: Hematology, Oncology ; Biochemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 494535244

The reversible post-translational modification of cellular proteins by the ubiquitin-related SUMO modifiers (SUMOylation) has emerged as a crucial regulatory mechanism in many cellular key pathways. SUMO signaling is instrumental for maintenance of genome integrity, control of gene expression and cell proliferation. The cellular SUMOylation status is tightly controlled by the balanced activity of the multi-step enzymatic SUMO conjugation machinery and the SUMO deconjugation pathway that primarily depends on SUMO-specific isopeptidases/proteases of the SENP family. Alterations of SUMO homeostasis are frequently observed in cancer, and associated with an aggressive phenotype. Enhanced SUMOylation is a therapeutic vulnerability for B-cell lymphoma (BCL) and solid cancers. Proteins can be monoSUMOylated at one or multiple lysine residues, but SUMO can also form polymeric chains on its substrates. polySUMO chains typically prime proteins for subsequent ubiquitylation by the SUMO-targeted Ubiquitin (Ub) ligase (StUbL) RNF4. The StUbL pathway is functionally connected to genome stability networks and DNA repair, where ubiquitylation by RNF4 typically controls the turnover of polySUMOylated repair factors at chromatin. RNF4 signaling is countered by the SUMO-specific isopeptidase SENP6, which functions as the primary enzyme for the trimming of SUMO chains. We have previously shown that genetic inactivation of SENP6 is linked to deficient DNA damage response and in particular affects ATR-CHK1 signaling in response to replicative stress, thereby conferring synthetic lethality to PARP inhibition. Intriguingly, we identified SENP6 as a candidate tumor suppressor (TS) in BCL by performing a global cancer gene discovery screen. We validated SENP6 as a functionally relevant TS in lymphoma with loss of SENP6 causing genome instability and an exceptional accumulation of polySUMO conjugates. Importantly, SENP6 deletions were identified in more than 30% of human aggressive BCLs and were associated with a MYC signature. Furthermore, low expression of SENP6 in diffuse large BCL (DLBCL) correlates with increased genome instability and poor prognosis. Altogether, these data indicate that unrestricted formation of SUMO chains causing unscheduled activation of the RNF4 pathway is a clinically relevant signaling event in BCL. We therefore propose the SENP6-RNF4 axis as a central hub controlling SUMO-ubiquitin crosstalk and multiple crucial aspects of cancer cell fate. Therapeutic intervention at this crucial node could thus provide an effective strategy in cancer therapy. Since the development of rational combination therapies for SENP6-deficient DLBCL requires a detailed mechanistic understanding of RNF4-SENP6-controlled DDR pathways we now aim to: i) identify tumor-relevant pathways and substrates affected by SENP6 loss in BCL; ii) decipher the role of RNF4 activation in BCL; iii) identify and deliver therapeutic strategies targeting the SENP6-RNF4 signaling axis.

• DFG Programme: Research Grants