SENP1/HIF-1α feedback loop modulates hypoxia-induced cell proliferation, invasion, and EMT in human osteosarcoma cells.

Hypoxia is an element intrinsic to most solid-tumor microenvironments, including that of osteosarcoma (OS), and is associated with resistance to therapy, poor survival, and a malignant phenotype. The purpose of the present study was to investigate the role and underlying mechanism of SUMO-specific protease 1 (SENP1)/hypoxia-inducible factor-1α (HIF-1α) feedback loop in hypoxic microenvironment of OS. We observed that the expression of SENP1 was remarkably upregulated in OS cells. Additionally, there was a concomitant high expression of HIF-1α and SENP1 in MG-63 cells under a hypoxic microenvironment. Interestingly, blockage of HIF-1α repressed the enhancement of SENP1. Moreover, knockdown of SENP1 with siRNA notably inhibited cell viability and accelerated cell apoptosis accompanied by a decrease in the expression of Bcl-2 and an increase in the expression of Bax in MG-63 cells following exposure to hypoxia. Furthermore, repression of SENP1 dramatically suppressed cell invasive ability through modulating epithelial-mesenchymal transition (EMT) marked genes as reflected by the upregulation of E-cadherin, as well as the downregulation of vimentin and N-cadherin under hypoxic conditions. Most importantly, SENP1 positively regulated HIF-1α expression level in the setting of hypoxic; subsequently, depletion of SENP1 expression markedly ameliorated vascular endothelial growth factor (VEGF) production triggered by hypoxia. Taken together, positive feedback loop between HIF-1α and SENP1 in the regulating of the process of cell proliferation, invasion, and EMT in OS cells under hypoxic conditions, suggesting that the SENP1/HIF-1α axis may serve as a new potential therapeutic agent for OS treatments.

Wang X ，Liang X ，Liang H ，Wang B ... -  《-》

Resveratrol abrogates the effects of hypoxia on cell proliferation, invasion and EMT in osteosarcoma cells through downregulation of the HIF-1α protein.

Sun Y ，Wang H ，Liu M ，Lin F ，Hua J ... -  《-》

Hypoxia maintains the fenestration of liver sinusoidal endothelial cells and promotes their proliferation through the SENP1/HIF-1α/VEGF signaling axis.

Liver sinusoidal endothelial cells (LSECs), which play a very critical role in liver regeneration, function in hypoxic environments, but few studies have elucidated the specific mechanism. As a hypoxia-sensitive gene, Sentrin/SUMO-specific protease 1(SENP1) is upregulated in solid tumors due to hypoxia and promotes tumor proliferation. We speculate that LSECs may upregulate SENP1 in hypoxic environments and that SENP1 may act on downstream genes to allow the cells to adapt to the hypoxic environment. To elucidate the reasons for the survival of LSECs under hypoxia, we designed experiments to explore the possible mechanism. First, we cultured murine LSECs in hypoxic conditions for a certain time (24 h and 72 h), and then, we observed that the proliferation ability of the hypoxia group was higher than that of the normoxia group, and the number of unique fenestrae of the LSECs in the hypoxia group was more than that of the LSECs in the normoxia group. Then, we divided the LSECs into several groups for hypoxic culture for time points (6 h, 12 h, 24 h, 36 h, and 72 h), and we found that the expression of SENP1, HIF-1α and VEGF was significantly upregulated. Then, we silenced SENP1 and HIF-1α with si-SENP1 and si-HIF-1α, respectively. SENP1, HIF-1α and VEGF were significantly downregulated, as determined by RT-PCR, WB and ELISA. Unexpectedly, the proliferation activity of the LSECs decreased and the fenestrae disappeared more in the si-SENP1 and si-HIF-1α groups than in the control group. It is concluded that LSECs cultured under hypoxic conditions may maintain fenestrae and promote proliferation through the SENP1/HIF-1α/VEGF signaling axis, thereby adapting to the hypoxic environment.

Qing Z ，Huang H ，Yang S ，Lin J ，Zeng Z ，Duan J ，Yuan B ，Ming T ... -  《-》

GRIM-19 repressed hypoxia-induced invasion and EMT of colorectal cancer by repressing autophagy through inactivation of STAT3/HIF-1α signaling axis.

Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. Thereby, the aim of the present study was to investigate the detailed effects of gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) in colorectal cancer (CRC) cell lines under hypoxia conditions and explore the potential molecular mechanisms. Here, we observed that GRIM-19 expression was downregulated in several CRC cell lines as well as in HCT116 and Caco-2 cells under a hypoxic microenvironment. Additionally, the introduction of GRIM-19 obviously suppressed cell invasive ability and epithelial-mesenchymal transition (EMT) through modulating EMT markers as reflected by the upregulation of E-cadherin along with the downregulation of vimentin and N-cadherin under hypoxic conditions. Moreover, the addition of GRIM-19 repressed hypoxia-induced autophagy through modulating autophagy associated proteins as reflected by the downregulation of LC3-II/LC3-I ratio and Beclin-1 expression, as well as the increased of p62 expression. Interestingly, overexpression of GRIM-19 markedly ameliorated the accumulation of HIF-1α triggered by hypoxia accompanied by an inhibition of vascular endothelial growth factor (VEGF) production and phospho-signal transducer and activator of transcription 3 (p-STAT3) expression. Further data demonstrated that GRIM-19 have a negative feedback effect on the expression of HIF-1α. Mechanistically, re-expression of HIF-1α completely reversed the inhibitory effects of GRIM-19 on hypoxia-induced invasion and EMT. Taken all data together, our findings established that GRIM-19 suppresses hypoxia-triggered invasion and EMT by inhibiting hypoxia-induced autophagy through inactivation HIF-1α/STAT3 signaling pathway, indicating that GRIM-19 may serve as a potential predictive factor and therapeutic target for CRC treatment.

Zhang J ，Chu D ，Kawamura T ，Tanaka K ，He S ... -  《-》

SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop.

We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α. Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.

Cui CP ，Wong CC ，Kai AK ，Ho DW ，Lau EY ，Tsui YM ，Chan LK ，Cheung TT ，Chok KS ，Chan ACY ，Lo RC ，Lee JM ，Lee TK ，Ng IOL ... -  《-》