Cancer cells acquire dysregulated gene expression to establish specific transcriptional dependencies and their underlying mechanisms that are ultimately responsible for this addictions have not been fully elucidated. Glucose‐regulated protein 78 (GRP78) is a stress‐inducible, multifunctional, prosurvival, endoplasmic reticulum chaperone in the heat shock protein 70 family. Expression of cell surface GRP78 (CS‐GRP78) is associated with increased malignant behavior and resistance to chemotherapy and radiotherapy by endowing various cancer cells with increased proliferative ability, altered metabolism, improved survival, and augmented invasive and metastatic potential. Emerging evidence has highlighted an unusual role of CS‐GRP78 in regulating transcription factors (TFs) by mediating various signaling pathways involved in malignant transformation, metabolic reprogramming, and tumor progression. During the last decade, we targeted CS‐GRP78 with C38 monoclonal antibody (C38 Mab) in numerous studies, which have highlighted the epigenetic interplay between CS‐GRP78 and various TFs including c‐MYC, Yes‐associated protein/transcriptional coactivator with PDZ‐binding motif, c‐Fos, and histone acetylation to potentiate subsequent modulation of tumorigenesis, invasion, and metastasis. Here, we summarize the current state of knowledge about the role of CS‐GRP78 in cancer development and progression, including epigenetic regulation and sheds light on CS‐GRP78 as vulnerable target for cancer therapy. Overall, this review focuses on the mechanisms of TFs that are behind the transcriptional dysregulation in cancer and lays the groundwork for rational therapeutic use of C38 Mab based on CS‐GRP78 biology.

中文翻译：

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细胞表面 GRP78 信号传导：在癌症中作为转录调节剂的新兴作用

癌细胞获得失调的基因表达以建立特定的转录依赖性，而最终导致这种成瘾的潜在机制尚未完全阐明。葡萄糖调节蛋白 78 (GRP78) 是热休克蛋白 70 家族中的一种应激诱导型、多功能、促存活、内质网伴侣蛋白。细胞表面 GRP78 (CS-GRP78) 的表达通过赋予各种癌细胞增殖能力增加、代谢改变、存活率提高以及侵袭和转移潜力增加，与恶性行为和对化疗和放疗的抵抗力增加有关。新出现的证据强调了 CS-GRP78 通过介导各种参与恶性转化的信号通路在调节转录因子 (TF) 中的不寻常作用，代谢重编程和肿瘤进展。在过去十年中，我们在许多研究中用 C38 单克隆抗体 (C38 Mab) 靶向 CS-GRP78，这些研究强调了 CS-GRP78 与各种 TF 之间的表观遗传相互作用，包括 c-MYC、Yes 相关蛋白/转录辅激活因子与 PDZ-结合基序、c-Fos 和组蛋白乙酰化以加强对肿瘤发生、侵袭和转移的后续调节。在这里，我们总结了关于 CS-GRP78 在癌症发展和进展中的作用的当前知识状态，包括表观遗传调控，并阐明 CS-GRP78 作为癌症治疗的脆弱靶点。总体而言，本综述重点关注癌症转录失调背后的 TF 机制，并为基于 CS-GRP78 生物学的 C38 Mab 合理治疗应用奠定基础。