Induction of heparanase 2 (Hpa2) expression by stress is mediated by ATF3

Knani, Ibrahim; Singh, Preeti; Gross-Cohen, Miriam; Aviram, Sharon; Ilan, Neta; Sanderson, Ralph D.; Aronheim, Ami; Vlodavsky, Israël

doi:10.1016/j.matbio.2021.11.001

Cited by 9 publications

(35 citation statements)

References 55 publications

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“…The expression level of the HPSE2 gene is low in most malignant cell lines [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Likewise, RMPI-8226 cells expressed a very low, but detectable level of HPSE2 and there was no effect to electrical pulse and transfection with an empty plasmid.…”

Section: Resultsmentioning

confidence: 99%

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Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Ostrovsky

Beider

Magen

et al. 2023

Cells

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Multiple myeloma (MM) is a plasma cell malignancy that is accompanied by hypercalcemia, renal failure, anemia, and lytic bone lesions. Heparanase (HPSE) plays an important role in supporting and promoting myeloma progression, maintenance of plasma cell stemness, and resistance to therapy. Previous studies identified functional single nucleotide polymorphisms (SNPs) located in the HPSE gene. In the present study, 5 functional HPSE SNPs and 11 novel HPSE2 SNPs were examined. A very significant association between two enhancer (rs4693608 and rs4693084), and two insulator (rs4364254 and rs4426765) HPSE SNPs and primary paraskeletal disease (PS) was observed. SNP rs657442, located in intron 9 of the HPSE2 gene, revealed a significant protective association with primary paraskeletal disease and lytic bone lesions. The present study demonstrates a promoting (HPSE gene) and protective (HPSE2 gene) role of gene regulatory elements in the development of paraskeletal disease and bone morbidity. The effect of signal discrepancy between myeloma cells and normal cells of the tumor microenvironment is proposed as a mechanism for the involvement of heparanase in primary PS. We suggest that an increase in heparanase-2 expression can lead to effective suppression of heparanase activity in multiple myeloma accompanied by extramedullary and osteolytic bone disease.

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Section: Resultsmentioning

confidence: 99%

“…The role of Hpa2 in the development of cancer is not well understood. However, heparanase-2 inhibits heparanase enzymatic activity [ 23 ] and appears to function as a tumor suppressor [ 19 , 24 , 25 , 26 , 27 , 28 , 29 ]. The role of heparanase-2 in multiple myeloma has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Ostrovsky

Beider

Magen

et al. 2023

Cells

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“…105,[107][108][109]113 Experimentally, overexpression of Hpa2 attenuated the growth of tumor xenografts, whereas Hpa2 gene silencing resulted in bigger tumors. [106][107][108][109]111,114,115 This is best demonstrated by gene editing of Hpa2 in pharyngeal FaDu cells applying the CRISPR technology. Notably, Hpa2-null cells produced bigger tumors vs control cells, whereas the rescue of Hpa2 in the null cells resulted in smaller tumors.…”

Section: Hpa2-a New Player In the Heparanase Fieldmentioning

confidence: 99%

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

Vlodavsky,

Kayal,

Hilwi

et al. 2023

Proteoglycan Research

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Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM‐bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor‐host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal‐based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase‐based therapy has not been implemented in the clinic. Unlike heparanase, heparanase‐2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS‐degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.

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“…Inducible expression of HPSE‐2 was also quantified in cells exposed to heat shock, proteotoxic stress, lysosomal stress, and chemotherapy. Specifically, analysis of the HPSE‐2 gene promoter identified ATF3 as the transcription factor mediating stress‐induced HPSE‐2, resulting in improved prognosis of cancer patients (Knani et al, 2022; Figure 5).…”

Section: The Antitumorigenic Role Of Hpse In Cancer Progressionmentioning

confidence: 99%

“…HPSE‐2, a close homolog of HPSE, lacks the enzymatic activity of HPSE and is capable of contributing to tumor suppression (Kayal et al, 2021; Vlodavsky et al, 2018). Stress‐induced HPSE‐2 expression mediated by activating transcription factor 3 (ATF3) may translate into improved survival in cancer patients (Knani et al, 2022). Given the pleiotropic roles of HPSE, the elucidation of the precise mechanism of HPSE in cancer progression is crucial for the development of cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

Potential roles of heparanase in cancer therapy: Current trends and future direction

Yang

Yuan

Zhou

et al. 2023

Journal Cellular Physiology

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Heparanase (HPSE; heparanase‐1) is an endo‐β‐glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase‐2 (HPSE‐2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro‐ and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.

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Induction of heparanase 2 (Hpa2) expression by stress is mediated by ATF3

Cited by 9 publications

References 55 publications

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

Potential roles of heparanase in cancer therapy: Current trends and future direction

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