PNA-mediated Inhibition of the SENP1 Molecular Hub as a Potential Therapeutic Approach for the Suppression of Osteosarcoma Growth and Metastasis (PNA-OS)

Background:

Osteosarcoma (OS) is the most common type of primary malignant bone tumor in children and adolescents. The overall survival rate is dramatically reduced by the development of metastases, often pulmonary. Solid malignant tumors, such as OS, often develop a hypoxic microenvironment, which contributes to tumor growth, metastasis, treatment failure, and patient mortality. Adaptation to hypoxia, as well as to other environmental conditions, is often associated with modifications in the post-transcriptional regulation of key effectors. Among these, SUMOylation is carried out by small ubiquitin-like modifier (SUMO) proteins and is dynamically reversed (deSUMOylation) by Sentrin/SUMO-specific proteases (SENPs). SENP1, the best characterized SENP, is upregulated in multiple tumors being involved in tumorigenesis and tumor progression. Through deSUMOylation, SENP1 acts as a molecular hub that stabilizes and activates key regulator factors, such as hypoxia-inducible factor 1α (HIF1α), zinc finger E-box binding homeobox 1 (ZEB1), and Akt, responsible for tumor cells adaptation to hypoxic microenvironment, induction of cell proliferation, invasion and migration, and inhibition of apoptosis, thus contributing to tumor progression and metastasis.

HIF1α is the master transcriptional regulator for cellular adaptation and survival under hypoxic conditions, and contributes to enhance the cell metastatic potential. SENP1-mediated HIF1α deSUMOylation prevents HIF1α degradation by proteasome, thus activating the HIF1α signaling pathway. SENP1 is overexpressed in OS cells under hypoxic condition and siRNA-mediated silencing of SENP1 decreases tumor cell viability, promotes cell apoptosis, reduces invasiveness, and inhibits the epithelial-mesenchymal transition (EMT).

ZEB1 is involved in tumorigenesis, progression, invasion and metastases in several tumors (e.g. glioblastoma, prostate, lung, liver, and colorectal). ZEB1 silencing in OS cells leads to a reduced caspase-3 activity, NF-κB and iNOS inhibition, overall reduced cell proliferation and increased apoptosis. SENP1 knockdown in hepatocellular carcinoma (HCC) cells decreases ZEB1 and inhibits EMT].

Akt hyper-activation is essential for the onset and progression of tumors, including OS. In astroglioma cells siRNA-mediated inhibition of SENP1 is associated to Akt hypophosphorylation accompanied by the inhibition of its downstream targets Bcl-xL and cyclinD1 and p21 upregulation, leading to cell-cycle arrest and increased apoptosis.