SENP1 promotes proliferation of clear cell renal cell carcinoma through activation of glycolysis

Abstract

Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC. Moreover, SENP1 knockdown in RCC4/VHL cells downregulated expression of key glycolytic enzymes under normoxic and hypoxic conditions and inhibited cell proliferation under hypoxic conditions, possibly due to ineffective deSUMOylation and stablization of Hif-1α related to the SENP-1 deficiency. Finally, SENP1 expression correlated positively with tumor pathological grade and was an indicator of poor overall survival and advanced tumor progression in ccRCC. Altered VHL gene function is found in 60–90% ccRCC cases of ccRCC, but therapies targeting VHL-related signaling pathways have been ineffective, spurring exploration of alternative pathological signaling events. Our results provide a possible mechanistic explanation for the role of SENP1 in the initiation and development of ccRCC with normal VHL activity, and identifies SENP1 as a potential treatment target for the disease.

Small ubiquitin‐like modifier/sentrin‐specific peptidase 1 associates with chemotherapy and is a risk factor for poor prognosis of non‐small cell lung cancer

“…Wang et al showed that increased SENP1 level in A549 cells promoted cell proliferation, while the inhibition of SENP1 induced G1 cell cycle arrest and radiosensitivity. Dong et al also reported that the knockdown of SENPs in clear cell renal cell carcinoma (ccRCC) cells inhibited cell proliferation. They revealed that the expression of SENP1 was positively correlated with pathological grades of ccRCC tumor, and the high expression of SENP1 was an indicator of poor overall survival and advanced ccRCC tumors .…”

“…Dong et al also reported that the knockdown of SENPs in clear cell renal cell carcinoma (ccRCC) cells inhibited cell proliferation. They revealed that the expression of SENP1 was positively correlated with pathological grades of ccRCC tumor, and the high expression of SENP1 was an indicator of poor overall survival and advanced ccRCC tumors . The results in our present study were consistent with those from Wang and Dong et al, showing that SENP1 was a risk factor for the poor prognosis of patients with NSCLC.…”

“…It has been reported that the overexpression and stabilization of HIF‐1α acts as an oncogenic actor by activating its downstream glycolytic enzymes and promoting glycolysis and glucose metabolism in tumor cells . The prolonged expression of HIF‐1α in cancer cells under hypoxic conditions promoted cell proliferation and metastasis, and enhanced the radioresistance of cancer cells .…”

“…Hypoxia‐inducible factor‐1 alpha activates downstream glycolytic enzyme‐encoding genes and promotes glycolysis and glucose metabolism, epithelial‐mesenchymal transition (EMT), and tumor metastasis . The overexpression of HIF‐1α is well known to be correlated with the poor overall survival of several cancers .…”

“…deSUMOylation enzyme which targets a number of key proteins for promoting the stabilization of hypoxia-inducible factor-1 alpha (HIF-1α). 9,10 The overexpression of SENP1 contributes to the abnormity of the cell nucleus and mitochondria. 11,12 It has been reported that the expression of SENP1 was upregulated in NSCLC.…”