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

Abstract

ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC 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.ResultsWe 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.ConclusionsTaken 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.

SENP1 activity sustains cancer stem cell in hypoxic HCC

“…By contrast, Cui et al ,8 by focusing their study on hypoxia-induced CSC subpopulation, revealed that deSUMOylation is required to promote the transcriptional activity of HIF-1α on stem cell genes (ie, CD24, Nanog and Oct3/4). Moreover, the authors demonstrated that deSUMOylation is required to promote and/or maintain CD24+ liver CSC population.…”

“…This means, in practical terms, that the regulatory role of SENP1 on hypoxia-induced enhancement of liver CSC properties is mechanistically dependent on its catalytic activity, making SENP1 a promising putative target for novel therapeutic approaches. Of interest, in their study Cui et al 8 failed to detect significant conjugation of SUMO with HIF-2α in HCC cells, contrary to what reported for HeLa cells in which HIF-2α was found to be regulated by SUMO and SENP1 10. Accordingly, although SENP1 is upregulated by hypoxia through the involvement of both HIF-1α and HIF-2α, only the knockdown of HIF-1α, but not of HIF-2α, partially suppressed SENP1-enhanced stemness of HCC cells in hypoxia.…”

“…In this issue, Cui et al 8 shed a further light on the correlation between HIF-1α (and, for some aspects, HIF-2α as well) and HCC progression, unveiling a new positive feedback loop involving HIF-1α subunit, overall suggesting the small ubiquitin-like modifier (SUMO) protease 1 (SENP1) as a novel putative therapeutic target for HCC. This message is of relevance since increasing evidence has shown that HIF-1α is an important SUMO substrate, although HIF-1α SUMOylation and related effects may vary among different cell types.…”

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

“…The overexpression of HIF‐1α is well known to be correlated with the poor overall survival of several cancers . The stable activity of SENP1 under hypoxia‐stressed hepatocellular carcinoma could sustain cancer stem cell stemness by promoting deSUMOylation and stabilization of HIF‐1α . SENP1 expression desensitizes cancer cells to chemoradiotherapy via the upregulation of HIF‐1α .…”

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

“…Its involvement in tissue morphogenesis (23) has been demonstrated in enterocytes (24), keratinocytes (25), and adipocytes (26,27). However, it also participates in human malignancy by favoring cancer cell stemness (28,29). Post-translational modification of target proteins by the covalent addition of small ubiquitin-like modifier (SUMO) 1-3 peptides to specific lysine residues involves an enzymatic cascade requiring the sequential action of the E1 heterodimer SUMOactivating enzyme (SAE) 1/2 for the activation step, the unique E2 enzyme ubiquitin-conjugating enzyme E2 I (UBE2I or UBC9) for the conjugation step, and various E3 ligation enzymes including protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS) 1-4, Ran GTPase binding protein 2, structural maintenance of chromosome 5-6 complex SUMO ligase, and chromobox 4 proteins that increases efficiency of the conjugation step (30).…”