Activity of heparanase, endoglycosidase that cleaves heparan sulfate side chains in heparan sulfate proteoglycans, is highly implicated in tumor progression and metastasis. Heparanase inhibitors are therefore being evaluated clinically as anti-cancer therapeutics. Heparanase 2 (Hpa2) is a close homolog of heparanase that lacks HS-degrading activity and functions as an endogenous inhibitor of heparanase. As a result, Hpa2 appears to attenuate tumor growth but mechanisms that regulate Hpa2 expression and determine the ratio between heparanase and Hpa2 are largely unknown. We have recently reported that the expression of Hpa2 is induced by endoplasmic reticulum (ER) and proteotoxic stresses, but the mechanism(s) underlying Hpa2 gene regulation was obscure. Here we expand the notion that Hpa2 is regulated by conditions of stress. We report that while ER and hypoxia, each alone, resulted in a 3-7 fold increase in Hpa2 expression, combining ER stress and hypoxia resulted in a noticeable, over 40-fold increase in Hpa2 expression. A prominent induction of Hpa2 expression was also quantified in cells exposed to heat shock, proteotoxic stress, lysosomal stress, and chemotherapy (cisplatin), strongly implying that Hpa2 is regulated by conditions of stress. Furthermore, analyses of the Hpa2 gene promoter led to the identification of activating-transcription-factor 3 (ATF3) as a transcription factor that mediates Hpa2 induction by stress, thus revealing, for the first time, a molecular mechanism that underlies Hpa2 gene regulation. Induction of Hpa2 and ATF3 by conditions of stress that often accompany the rapid expansion of tumors is likely translated to improved survival of cancer patients.

乙酰肝素酶的活性，即裂解硫酸乙酰肝素蛋白聚糖中硫酸乙酰肝素侧链的内切糖苷酶，与肿瘤进展和转移密切相关。因此，乙酰肝素酶抑制剂正在作为抗癌疗法进行临床评估。乙酰肝素酶 2 (Hpa2) 是乙酰肝素酶的密切同系物，缺乏 HS 降解活性，可作为乙酰肝素酶的内源性抑制剂。结果，Hpa2 似乎减弱了肿瘤生长，但调节 Hpa2 表达和决定乙酰肝素酶与 Hpa2 之间比率的机制在很大程度上是未知的。我们最近报道 Hpa2 的表达是由内质网 (ER) 和蛋白毒性应激诱导的，但 Hpa2 基因调控的潜在机制尚不清楚。在这里，我们扩展了 Hpa2 受压力条件调节的概念。我们报告说，虽然 ER 和缺氧单独导致 Hpa2 表达增加 3-7 倍，但结合 ER 应激和缺氧导致 Hpa2 表达显着增加超过 40 倍。在暴露于热休克、蛋白毒性应激、溶酶体应激和化学疗法（顺铂）的细胞中也量化了 Hpa2 表达的显着诱导，强烈暗示 Hpa2 受应激条件的调节。此外，对 Hpa2 基因启动子的分析导致将激活转录因子 3 (ATF3) 鉴定为介导压力诱导 Hpa2 的转录因子，从而首次揭示了 Hpa2 基因调控的分子机制。