Differential expression of SUMO-specific protease 7 variants regulates epithelial–mesenchymal transition

Abstract

Two Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 7 (SENP7) variants are naturally expressed in breast epithelia. Breast cancer (BCa) onset down-regulates the short SENP7 splice variant (SENP7S) and enhances the long transcript (SENP7L). Here, we show that SENP7L induction promotes gene expression profiles that favor aberrant proliferation and initiate epithelial-mesenchymal transition (EMT). SENP7L exhibits an interaction domain for the epigenetic remodeler heterochromatin protein 1 α (HP1α) and isopeptidase activity against SUMO-modified HP1α. Loss of this interaction domain, as observed with SENP7S, favors HP1α SUMOylation. SUMOylated HP1α is enriched at E2F-responsive and mesenchymal gene promoters, silences transcription of these genes, and promotes cellular senescence. Elevated SENP7L renders HP1α hypo-SUMOylated, which relieves transcriptional repression of the same genes and concurrently decreases transcription of epithelial-promoting genes via an HP1α-independent mechanism. Consequently, SENP7L levels correlate with EMT, motility, and invasiveness of BCa cells. Stable knockdown of elevated SENP7L levels lessens the dissemination of highly metastatic BCa cells to the lungs from primary implantation sites in in vivo studies. Thus, differential splicing of the SENP7 regulates either tumor suppression or progression.posttranslational-modification | epigenetics | dedifferentiation P osttranslational modification by the small ubiquitin-like modifier (SUMO) family has garnered much attention in cancer biology. This could be attributed to the ability of SUMOylation to elicit a rapid and reversible change to a protein's function and/or subcellular localization. However, SUMOylation of one cellular target may be critical for normal cell physiology, whereas SUMO conjugation of another protein may promote aberrant growth. Hence, targeting the SUMO-conjugating machinery may be detrimental to cancer as well as normal cells.Recently, the interest has shifted to the SUMO deconjugating enzymes or Sentrin/SUMO-specific proteases (SENP), which exhibit isopeptidase activity against a select subset of SUMOylated substrates. Although the expression of several SENPs is altered with onset of various carcinomas (1, 2), the physiological and/or pathophysiological function of many of the SENPs remains undefined. In addition, the six mammalian SENPs exhibit multiple splice variants that add to the functional diversity of the individual enzymes. SENP7 is an ideal example. Our laboratory used both extrinsic and experimental approaches to identify an SENP7 gene transcript with an intact catalytic domain (3). Recent studies show that the catalytic domain of SENP7 exhibits activity against synthetic and endogenous SUMO-conjugated substrates (4-6). Although these studies demonstrate SENP7's deSUMOylating capabilities, there exists a paucity of literature on the biological function of SENP7. In the present article we characterize two SENP7 transcript variants whose dueling functions support either tumor suppressive or po...

Beyond the histone tale: HP1α deregulation in breast cancer epigenetics

“…1). [34][35][36][37][38] Many different types of proteins contain PxVxL motifs, and several have been shown to interact with HP1 proteins through the CSD: specific examples include TIF1a and TIF1b, 17,18,39 the lamin B receptor, 40 the nuclear body component SP100, 41 the SUMO-specific protease SENP7, 42 and the chromatin assembly factor 1 subunit p150 (CAF-1p150). 43 However, there are proteins that associate with the CSD of HP1 through alternative sequence motifs, such as BRM-related gene 1 (BRG1) and pogo transposable element-derived protein with zinc finger domain (POGZ).…”

“…the EMT mesenchymalmarker vimentin) in poorly invasive epithelial cells. 42 Elevated SENP7 levels mediate an HP1a hypo-sumoylation, which abolish the silencing of these E2F-responsive and mesenchymal gene promoters, and concordantly is involved in acquisition of the EMT-like phenotype. 42 A putative not yet solved underlying complexity for the SENP7 and HP1a association to mediate gene regulated is illustrated by Maison, et al finding that SENP7 mediated de-conjugation of HP1a sumoylation can be involved in retention of the initial targeted sumoylated HP1a to pericentric heterochromatin (Fig.…”

“…55 A recent report has specifically addressed the important link between HP1a sumoylation, heterochromatin remodeling and EMT. 42 The SENP7 SUMO-specific protease is involved in breast cancer progression and interacts with the HP1a CSD through a PxVxL motif. 42,112 Sumoylated HP1a is enriched at, and silences, E2F-responsive and mesenchymal gene promoters (i.e.…”

“…42 The SENP7 SUMO-specific protease is involved in breast cancer progression and interacts with the HP1a CSD through a PxVxL motif. 42,112 Sumoylated HP1a is enriched at, and silences, E2F-responsive and mesenchymal gene promoters (i.e. the EMT mesenchymalmarker vimentin) in poorly invasive epithelial cells.…”

Suv39h1 links the SUMO pathway to constitutive heterochromatin

“…In this respect, the SUMO-specific protease SENP7 localized at pericentric heterochromatin is a likely candidate, in particular given its ability to bind to HP1 proteins 8 and its reported involvement in tumorigenesis. 9 Therefore, 2 steps emerge as critical in the organization of constitutive heterochromatin: a "seeding" step requiring HP1a sumoylation and a "propagation/maintenance" step involving H3K9me3. This sequential mechanism provides a molecular basis for both the establishment and maintenance of pericentric constitutive heterochromatin (Fig.…”