Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity

Abstract

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

Distinct expression pattern and prognostic values of pituitary tumor transforming gene family genes in non‑small cell lung cancer

“…The PTTG family, which comprises PTTG1, PTTG2 and PTTG3P, is a newly identified gene class. Among the three homologous genes, PTTG1 has been the most extensively studied and has been identified to be closely associated with the onset and progression of multiple human cancer types, including pituitary tumor (22), malignant glioma (7), thyroid (23), breast (24), ovarian (25), bladder (8), prostate (9) and lung cancer (26–30). Honda et al (30) have demonstrated that PTTG1 is significantly upregulated in NSCLC and its overexpression serves a role in the genesis and progression of NSCLC.…”

Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

“…RSUME is a novel and important player in pituitary tumor pathogenesis. RSUME also acts on the HPA axis at the pituitary stage, increasing pituitary tumor transforming gene (PTTG) protein stability ( 9 ) ( Figure 1B ). PTTG is the vertebrate securin ( 34 , 35 ) whose overexpression correlates with tumor invasiveness and recurrence.…”

“…This explains the effect of RSUME modulating PTTG high protein levels that account for PTTG tumor abundance and demonstrates an important role of RSUME in tumor cells of the pituitary. Regarding the molecular mechanism, we have described that PTTG protein levels decrease when the SUMOylation pathway is inhibited by the viral Gam1 protein ( 37 ), and the consequent reversal of this effect when an inactive mutant is used ( 9 ), suggesting that SUMO signaling is involved in the stabilization of PTTG. For many proteins, SUMOylation could protect them from degradation by the ubiquitin/proteasome system, in addition to increasing their stability, changing their subcellular localization or distribution, and/or modifying their molecular interactions.…”

Mouse models of endocrine tumors

“…Indeed, in recent years, mice xenografts have been widely used to characterize the responses to drugs currently prescribed for these pathologies as lanreotide (Ning et al 2009), thiazolidinediones (Mannelli et al 2010), bromocriptine and/or cabergoline (Lin et al 2017) or to alternative therapies such as metformin , histone deacetylase inhibitor SAHA (Lu et al 2017), Liquiritigenin (Wang et al 2014), Triptolide (Li et al 2017) or Bafilomycin A1 (McSheehy et al 2003), which have been shown to exhibit antitumoral roles in these pathologies. Likewise, PAs xenograft models have also been used to characterize the function of different pathways, genes and relevant mutations in several types of PAs, as Fgfr4 in intracranial xenograft mouse models (Ezzat et al 2006, Jalali et al 2016, inactivating mutations of Pit-1 (Roche et al 2012), overexpression of Lrig1 (Cheng et al 2016) or Meg3 (Chunharojrith et al 2015), persistent activation of the Ras/MAPK pathway (Booth et al 2014), antitumoral actions of miR-524-5p (Zhen et al 2017) and role of RSUME in PTTG protein stabilization (Fuertes et al 2018). Finally, PDX models have been sparsely implemented in the case of PAs.…”