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SENP Proteases As Potential Targets for Cancer Therapy cancers Review SENP Proteases as Potential Targets for Cancer Therapy Paulina Tokarz * and Katarzyna Wo´zniak Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-635-48-15; Fax: +48-42-635-44-84 Simple Summary: Post-translational modification—the biochemical addition of functional groups or proteins—occurs following protein biosynthesis and contributes to an increase in the functional diversity of the proteome. Post-translational modifications include SUMOylation—the covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMOylation is a reversible modification, which is erased by SUMO-specific proteases (SENPs). Deregulation of SENPs leads to cellular dysfunction and is associated with various diseases, including cancer. The role of SENPs in cancer pathogenesis is expected, and thus these proteins are considered promising targets for drug design and development. In this review, we will discuss the role of SENPs, focusing on DNA repair and the cell cycle—cellular pathways malfunctioning in most cancer cells—and provide an update on advances in the development of SENP-oriented inhibitors. Abstract: SUMOylation is a reversible post-translational modification (PTM) involving a covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMO-specific proteases (SENPs) are cysteine proteases with isopeptidase activity facilitating the de-conjugation of SUMO proteins and thus participating in maintaining the balance between the pools of SUMOylated and unSUMOylated proteins and in SUMO recycling. Several studies have reported that SENPs’ aberrant expression is associated with the development and progression of cancer. In this review, Citation: Tokarz, P.; Wo´zniak,K. we will discuss the role of SENPs in the pathogenesis of cancer, focusing on DNA repair and the SENP Proteases as Potential Targets cell cycle—cellular pathways malfunctioning in most cancer cells. The plausible role of SENPs for Cancer Therapy. Cancers 2021, 13, in carcinogenesis resulted in the design and development of their inhibitors, including synthetic 2059. https://doi.org/10.3390/ protein-based, peptide-based, and small molecular weight inhibitors, as well as naturally occurring cancers13092059 compounds. Computational methods including virtual screening have been implemented to identify a number of lead structures in recent years. Some inhibitors suppressed the proliferation of prostate Academic Editor: Thomas Reinheckel cancer cells in vitro and in vivo, confirming that SENPs are suitable targets for anti-cancer treatment. Further advances in the development of SENP-oriented inhibitors are anticipated toward SENP Received: 19 March 2021 isoform-specific molecules with therapeutic potential. Accepted: 21 April 2021 Published: 24 April 2021 Keywords: SENP proteases; SUMOylation; deSUMOylation; DNA repair; cell cycle; cancer progres- sion; SENP inhibitors Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction SUMO-mediated signaling is an entire proteome regulating pathway that has a crucial role in maintaining cellular physiology. SUMOylation is a highly dynamic, reversible modification, catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (E3) enzymes (Figure1). Deregulation of SUMOylation and deSUMOylation balance causes This article is an open access article severe defects in cell proliferation and genome stability [1–4]. Therefore, it is not surpris- distributed under the terms and ing that SUMOylation needs to be tightly regulated to prevent malignant transformation. conditions of the Creative Commons SENPs conduct both processing of SUMO preproteins and deconjugation of SUMO from Attribution (CC BY) license (https:// target proteins (Figure1). The overexpression and genetic variation of SENPs have been creativecommons.org/licenses/by/ reported in malignant cancers (Table1). RNA-seq data from The Cancer Genome Atlas 4.0/). (TCGA) indicate that all SENPs are overexpressed in thyroid, lung, colorectal, head and Cancers 2021, 13, 2059. https://doi.org/10.3390/cancers13092059 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 15 Cancers 2021, 13, 2059 2 of 15 have been reported in malignant cancers (Table 1). RNA-seq data from The Cancer Ge- nome Atlas (TCGA) indicate that all SENPs are overexpressed in thyroid, lung, colorectal, neck,head stomach, and neck, liver, stomach, pancreatic, liver, renal,pancreatic, urothelial, renal, prostate, urothelial, testis, prostate, breast, testis, cervical, breast, endome- cervi- trial,cal, andendometrial, ovarian cancers; and ovarian glioma, cancers and melanoma.; glioma, and The melanoma.SENP2 gene The maps SENP2 to chromosome gene maps to 3q26-29,chromosome a region 3q26 commonly-29, a region amplified commonly in epithelial amplified cancers, in epithelial including cancers, lung, including esophagus, lung, headesophagus, and neck, head cervical, and neck, and cervical, ovarian and cancers ovarian [5]. Predominantly,cancers [5]. Predominantly, the overexpression the overex- of SENPspression is reportedof SENPs in is cancer, reported but in the cancer, down-regulation but the down is observed-regulatio inn someis observed types. in TCGA some alsotypes. indicates TCGA thatalso eachindicates SENP that can each serve SENP as a prognosticcan serve as marker a prognostic for specific marker cancer for specific types (Tablecancer1). types The diversity (Table 1). of The cancers diversity with dysregulatedof cancers with SENPs dysregulated suggests thatSENPs these suggests proteases that playthese a roleproteases in pathways play a generallyrole in pathways malfunctioning generally in malfuncti cancer ratheroning than in cancer participating rather than in tissue-specificparticipating pathways.in tissue-specific Indeed, pathways. SENPs regulated Indeed, suchSENPs pathways regulated as such DNA pathways repair, cell as cycle,DNA and repair, neovascularization, cell cycle, and neovascularization, indicating that the indicating aberrant function that the ofaberrant SENPs function works as of aSENPs cancer works driver as affecting a cancer the driver homeostasis affecting ofthe SUMO-mediated homeostasis of SUMO signaling.-mediated The studysignaling. in miceThe demonstratedstudy in mice demonstrated that prolonged that SENP1 prolonged overexpression SENP1 overexpression is critical for transformingis critical for trans- the normalforming prostate the normal gland, prostate and gradually gland, and facilitates gradually the facilitates onset of high-grade the onset of prostatic high-grade intraep- pros- ithelialtatic intraepithelial neoplasia [1]. neoplasia Moreover, [ the1]. Moreover, overexpression the overexpression of SENP1 was reportedof SENP1 in was precancerous reported in prostateprecancerous intraepithelial prostate neoplasiaintraepithelial in humans, neoplasia confirming in humans, that confirming SENP1 plays that a SENP1 role in can-plays cera role transformation. in cancer transformation. SENPs’ overexpression SENPs’ overexpression positively correlated positively with correlated clinicopathological with clinico- featurespathological such asfeatures TNM such stage, as tumor TNM differentiation,stage, tumor differentiation, lymph node lymph metastasis, node cancermetastasis, ag- gressiveness,cancer aggressiveness, and recurrence and recurrence (Table1). (Table In several 1). In cancers,several cancers, SENPs SENPs overexpression overexpression can servecan serve as a prognostic as a prognostic marker marker (Table (Table1). Mechanistic 1). Mechanistic studies studies demonstrated demonstrated that silencingthat silenc- SENPsing SENPs suppresses suppresses cancer cancer progression progression and and metastasis metastasis [6– 14[6–].14] The. The expression expression of of SENPs SENPs 0 cancan be be endogenously endogenously regulated regulated as as demonstrated demonstrated by by the the direct direct interaction interaction between between the the 3 3′ untranslateduntranslated region region of of SENP1 SENP1 mRNA mRNA and and microRNA-145 microRNA-145 (miR-145), (miR-145), a a significant significant miRNA miRNA tumortumor suppressor suppressor [4 [].4] miR-145-mediated. miR-145-mediated down-regulation down-regulation of of SENP1 SENP1 induced induced quiescence quiescence ofof prostate prostate cancer cancer cells cells andand reversedreversed SENP1-promotedSENP1-promoted tumorigenesis in in mice, mice, pointing pointing to tomiR miR-145-145 as as a amolecule molecule of of therapeutic therapeutic value value against against cancer. cancer. Apart Apart from from slowing slowing down down tu- tumormor growth, growth, silencing silencing of SENP cancan sensitizesensitize cellscells toto anticanceranticancer therapy. therapy. Knockdown Knockdown of of SENP6SENP6 induced induced radiosensitization radiosensitization of of liver liver cancer cancer cells cells [15 [15]. ]. Figure 1. SUMOylation and deSUMOylation mechanism. Sentrin-specific proteases (SENP) have Figure 1. SUMOylation and deSUMOylation mechanism. Sentrin-specific proteases (SENP) have endopeptidase activity to cleave SUMO (S) preproteins, exposing their carboxy-terminal diglycine endopeptidase activity to
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