Hull Elizabeth E, Montgomery McKale R, Leyva Kathryn J
Biomedical Sciences Program, College of Health Sciences, Midwestern University, Glendale, AZ 85308, USA.
Department of Microbiology & Immunology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
Int J Mol Sci. 2017 Jun 26;18(7):1361. doi: 10.3390/ijms18071361.
Emerging evidence suggests that the enzymes in the biosynthetic pathway for the synthesis of heparan sulfate moieties of heparan sulfate proteoglycans (HSPGs) are epigenetically regulated at many levels. As the exact composition of the heparan sulfate portion of the resulting HSPG molecules is critical to the broad spectrum of biological processes involved in oncogenesis, the epigenetic regulation of heparan sulfate biosynthesis has far-reaching effects on many cellular activities related to cancer progression. Given the current focus on developing new anti-cancer therapeutics focused on epigenetic targets, it is important to understand the effects that these emerging therapeutics may have on the synthesis of HSPGs as alterations in HSPG composition may have profound and unanticipated effects. As an introduction, this review will briefly summarize the variety of important roles which HSPGs play in a wide-spectrum of cancer-related cellular and physiological functions and then describe the biosynthesis of the heparan sulfate chains of HSPGs, including how alterations observed in cancer cells serve as potential biomarkers. This review will then focus on detailing the multiple levels of epigenetic regulation of the enzymes in the heparan sulfate synthesis pathway with a particular focus on regulation by miRNA and effects of epigenetic therapies on HSPGs. We will also explore the use of lectins to detect differences in heparan sulfate composition and preview their potential diagnostic and prognostic use in the clinic.
新出现的证据表明，硫酸乙酰肝素蛋白聚糖（HSPGs）硫酸乙酰肝素部分生物合成途径中的酶在多个水平上受到表观遗传调控。由于所得HSPG分子硫酸乙酰肝素部分的确切组成对于肿瘤发生所涉及的广泛生物过程至关重要，因此硫酸乙酰肝素生物合成的表观遗传调控对许多与癌症进展相关的细胞活动具有深远影响。鉴于当前专注于开发以表观遗传靶点为重点的新型抗癌疗法，了解这些新兴疗法可能对HSPGs合成产生的影响非常重要，因为HSPG组成的改变可能会产生深远且意想不到的影响。作为引言，本综述将简要总结HSPGs在广泛的癌症相关细胞和生理功能中所起的各种重要作用，然后描述HSPGs硫酸乙酰肝素链的生物合成，包括癌细胞中观察到的改变如何作为潜在的生物标志物。本综述随后将重点详细阐述硫酸乙酰肝素合成途径中酶的多重表观遗传调控水平，特别关注miRNA的调控以及表观遗传疗法对HSPGs的影响。我们还将探讨使用凝集素来检测硫酸乙酰肝素组成的差异，并展望它们在临床中的潜在诊断和预后用途。
