Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Abstract

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.

Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy

“…Based on CHISEL algorithm, they reanalyzed 10× genomics chromium single-cell DNA sequencing data from two patients at early stage of breast cancer (patient 1: a triple negative ductal carcinoma in situ and patient 2: at stage 1 infiltrating ductal carcinoma) and identified large-scale allele-specific copy-number aberrations (CNAs) which, on average, cover ~25% of the genome in at least 100 cells however were uncharacterized by previous used total copy-number analysis. Further investigation into the ~25% CNAs of the genome revealed that the most common type of allele-specific CNAs identified by CHISEL are copy-neutral LOHs and contains several genes which have been reported in the previous 560 breast cancer database [ 114 ], such as ARID1B and ESR1 on chromosome 6q, PTEN on chromosome 10q, BRCA2 and RB1 on chromosome 13, It is worth noting that all the genes undergoing copy-neutral LOHs have been reported in almost all type of tumor cells [ 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ], indicating that these copy-neutral LOHs mutations may take an important role at an early stage during the tumor evolution.…”

Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

“…Autophagy induced by lysosomal HPSE has been shown to enhance tumour development and chemoresistance [ 108 , 109 , 110 ]. Although HPSE activity has been mainly described extracellularly or within the cytoplasm, nuclear HPSE has also been reported [ 111 , 112 , 113 ]. In melanoma, nuclear HPSE was shown to suppress tumour progression by competing for DNA binding and inhibiting the transcription of genes, such as those coding for ECM-degrading enzymes that promote metastasis formation [ 112 ].…”

“…In melanoma, nuclear HPSE was shown to suppress tumour progression by competing for DNA binding and inhibiting the transcription of genes, such as those coding for ECM-degrading enzymes that promote metastasis formation [ 112 ]. In multiple myeloma disease context, HSPE was recently associated with chromatin opening and transcriptional activity concomitant with downregulation of PTEN tumour suppressor activity [ 111 ]. Also supporting the role of HPSE in tumour progression and metastasis formation, HPSE has been shown to promote EV secretion by tumour cells, affecting its protein cargo [ 114 , 115 ], and modulating HS structure on recipient cells to facilitate EVs internalisation [ 9 , 115 , 116 ].…”

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

“…Accumulating evidence suggests a role for heparanase in regulating gene transcription also through epigenetic mechanisms [30,79,[91][92][93][94][95][96][97]. Nuclear localization of heparanase, documented in several studies [34,35,96,97] has been associated with increased histone acetylation due to degradation of nuclear HS which acts as inhibitor of HATs [34,35]. To explore the role of the heparanase/ HPSG axis in epigenetic regulation in SS cells, we first examined the effect of heparanase on histone acetylation.…”

“…A deregulated heparanase/HSPG system profoundly impacts on tumor aggressiveness by acting both in the tumor microenvironment and inside the tumor cells. Emerging evidence indicates that nuclear heparanase and HSPGs also play a role in regulating histone acetylation and gene expression [33][34][35]. A potential relationship between deregulated heparanase/HSPG axis and oncogenic players in the different sarcoma subtypes remains to be elucidated.…”