Ling Hongbo, Li Yixuan, Peng Changmin, Yang Shengyu, Seto Edward
George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA.
Department of Cellular and Molecular Physiology, Penn State Cancer Institute, The Penn State University, 400 University Drive, Hershey, PA 17033, USA.
NAR Cancer. 2024 Apr 22;6(2):zcae018. doi: 10.1093/narcan/zcae018. eCollection 2024 Jun.
Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.
富含半胱氨酸的酸性分泌蛋白（SPARC）是一种保守的分泌糖蛋白，在调节各种生物学过程中发挥着关键作用。SPARC在几种癌症类型中高度表达，包括黑色素瘤，具有深远影响。了解癌症中控制SPARC表达的机制有可能改善癌症诊断、预后、治疗策略和患者预后。在此，我们证明组蛋白去乙酰化酶10（HDAC10）是黑色素瘤细胞中SPARC表达的关键调节因子。HDAC10的缺失或抑制会上调SPARC表达，而HDAC10的过表达则会下调SPARC表达。从机制上讲，HDAC10与组蛋白乙酰转移酶p300协同作用，调节调控元件处组蛋白H3赖氨酸27（H3K27ac）的乙酰化状态，并使含溴结构域蛋白4（BRD4）募集到这些区域，从而微调转录。HDAC10的缺失及由此导致的SPARC上调主要通过激活AMPK信号通路和诱导自噬来抑制黑色素瘤细胞生长。此外，HDAC10缺失导致的SPARC上调部分解释了耐药细胞对BRAF抑制剂的重新敏感。我们的研究揭示了HDAC10通过间接组蛋白修饰在基因调控中的作用，并提出了一种通过靶向HDAC10和SPARC治疗黑色素瘤或其他癌症的潜在策略。
