Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
Mol Oncol. 2018 May;12(5):724-755. doi: 10.1002/1878-0261.12195. Epub 2018 Apr 16.
Deletions of chromosome 1p36 are common in cancers; however, despite extensive studies, there has been limited success for discovering candidate tumor suppressors in this region. SRARP has recently been identified as a novel corepressor of the androgen receptor (AR) and is located on chromosome 1p36. Here, bioinformatics analysis of large tumor datasets was performed to study SRARP and its gene pair, HSPB7. In addition, using cancer cell lines, mechanisms of SRARP and HSPB7 regulation and their molecular functions were investigated. This study demonstrated that SRARP and HSPB7 are a gene pair located 5.2 kb apart on 1p36.13 and are inactivated by deletions and epigenetic silencing in malignancies. Importantly, SRARP and HSPB7 have tumor suppressor functions in clonogenicity and cell viability associated with the downregulation of Akt and ERK. SRARP expression is inversely correlated with genes that promote cell proliferation and signal transduction, which supports its functions as a tumor suppressor. In addition, AR exerts dual regulatory effects on SRARP, and although an increased AR activity suppresses SRARP transcription, a minimum level of AR activity is required to maintain baseline SRARP expression in AR+ cancer cells. Furthermore, as observed with SRARP, HSPB7 interacts with the 14-3-3 protein, presenting a shared molecular feature between SRARP and HSPB7. Of note, genome- and epigenome-wide associations of SRARP and HSPB7 with survival strongly support their tumor suppressor functions. In particular, DNA hypermethylation, lower expression, somatic mutations, and lower copy numbers of SRARP are associated with worse cancer outcome. Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis. In summary, SRARP and HSPB7 are tumor suppressors that are commonly inactivated in malignancies. SRARP inactivation is an early event in carcinogenesis that is strongly associated with worse survival, presenting potential translational applications.
1p36 染色体缺失在癌症中很常见；然而，尽管进行了广泛的研究，在该区域发现候选肿瘤抑制因子的成功率有限。SRARP 最近被鉴定为雄激素受体 (AR) 的新型核心抑制剂，位于 1p36 上。在这里，对大型肿瘤数据集进行了生物信息学分析，以研究 SRARP 及其基因对 HSPB7。此外，使用癌细胞系研究了 SRARP 和 HSPB7 的调节机制及其分子功能。这项研究表明，SRARP 和 HSPB7 是位于 1p36.13 上相距 5.2kb 的基因对，在恶性肿瘤中缺失和表观遗传沉默失活。重要的是，SRARP 和 HSPB7 在与 Akt 和 ERK 下调相关的集落形成和细胞活力中具有肿瘤抑制功能。SRARP 表达与促进细胞增殖和信号转导的基因呈负相关，这支持了其作为肿瘤抑制因子的功能。此外，AR 对 SRARP 具有双重调节作用，虽然增加的 AR 活性抑制 SRARP 转录，但 AR+癌细胞中维持基线 SRARP 表达需要最低水平的 AR 活性。此外，与 SRARP 一样，HSPB7 与 14-3-3 蛋白相互作用，呈现出 SRARP 和 HSPB7 之间的共同分子特征。值得注意的是，SRARP 和 HSPB7 与生存的全基因组和全表观基因组关联强烈支持它们的肿瘤抑制功能。特别是，SRARP 的 DNA 高甲基化、表达降低、体细胞突变和拷贝数降低与癌症预后较差相关。此外，正常相邻组织中 SRARP 的 DNA 高甲基化和表达降低预示着不良的生存，这表明 SRARP 失活是致癌作用的早期事件。总之，SRARP 和 HSPB7 是常见的肿瘤抑制因子，在恶性肿瘤中失活。SRARP 失活是致癌作用的早期事件，与较差的生存密切相关，具有潜在的转化应用。
