Nuclear protein 1 imparts oncogenic potential and chemotherapeutic resistance in cancer

Abstract

Nuclear protein 1 (NUPR1) also known as p8 and candidate of metastasis 1 (COM1) functions as a transcriptional regulator, and plays a role in cell cycle, DNA damage response, apoptosis, autophagy, and chromatin remodeling in response to various cellular stressors. Since it was first suggested to contribute to cancer development and progression in 1999, a number of studies have sought to reveal its function. However, NUPR1 and its biological relevance in cancer have proven difficult to pinpoint. Based on evidence of NUPR1 expression in cancers, its function extends from carcinogenesis and tumorigenesis to metastasis and chemotherapeutic resistance. A tumor suppressive function of NUPR1 has also been documented in multiple cancers. By and large, literature involving NUPR1 and cancer is confined to pancreatic and breast cancers, yet significant progress has been made with respect to NUPR1 expression and its function in lung, colorectal, blood, and prostate cancers, among others. Recent evidence strongly supports the notion that NUPR1 is key in chemotherapeutic resistance by mediating both anti-apoptotic activity and autophagy when challenged with anti-cancer compounds. Therefore, it is of significant importance to understand the broad range of molecular functions directed by NUPR1. In this review, NUPR1 expression and its role in breast, lung, and colorectal cancer development and progression will be addressed.

Keywords: Breast cancer; Chemotherapeutic resistance; Colorectal cancer; Lung cancer; NUPR1.

Figure 1.

NUPR1 and the Epigenetic Landscape in Breast, Lung, and Colorectal Cancers. LncRNA FAL1 is overexpressed in colorectal cancer, and acts as a ‘sponge’ for miR-637, which negatively regulates NUPR1 expression. Similarly, oncRNA T3p binds to and inhibits miR-10b and miR-387c, which both negatively regulate NUPR1 expression in breast cancer. NUPR1 contributes to Cr(VI)-mediated cell transformation and carcinogenesis in lung cancer by negatively regulating MOF, resulting in reduced levels of H4K16ac and corresponding gene expression. NUPR1 increases H3K4me3, a well-known transcriptional activation mark. Created with BioRender.com.

Figure 2.

Mechanisms of NUPR1-mediated Chemotherapeutic Resistance in Breast, Lung, and Colorectal Cancers. (left) NUPR1 is induced when challenged with chemotherapeutics doxorubicin and paclitaxel. NUPR1 controls p21 localization by mediating p21 phosphorylation in a PI3K/AKT-dependent manner. NUPR1 upregulates p21, which was shown to require p53 and p300, resulting in the upregulation of p21 target gene, BCL2L1 (i.e. BCL-XL). (middle) NUPR1 is induced by chemotherapeutic oxaliplatin, and induces ER stress, ROS generation, and autophagy. NUPR1 engages in a positive feedback loop with ER stress protein ATF4, and transcriptionally regulates ER stress protein CHOP. (right) NUPR1 mediates autolysosomal processing, and transcriptionally regulates SNAP25, which together with VAMP8, can impact autolysosomal efflux. NUPR1 dysregulation in cancer impacts p62, p21, and p27 expression. Created with BioRender.com.