Harnessing the alarmin HMGN1 for anticancer therapy.

Abstract

Incipient cancer cells formed as a result of mutations of oncogene(s), tumor suppressor gene(s) and/or DNA repair gene(s) develop into malignant tumors depending on three processes. They acquire a higher rate of mutation due to increased sensitivity to endogenous and exogenous mutagenic agents or due to a breakdown in one or several components of the DNA repair machinery [1]. They need to be induced to grow by hormones, cytokines and other mitogenic signals and achieve replicative immortality. Finally, the host’s immunosurveillance function fails because of immunoediting [2] and formation of an immunossupressive tumor microenvironment, resulting in preventing the immune control or rejection of the cancers [1,2]. Reagents that interfere with any of these processes have been identified as potential anticancer therapeutics [1]. We have shown the high mobility group nucleosome-binding protein 1 (HMGN1) to have a combination of activities that potentially counters the mutagenic and immunosuppressive properties of cancers. HMGN1 is a chromatin-binding nuclear protein and that can act as an extracellular alarmin. In this respect, HMGN1 is similar to the well known alarmin, HMGB1. Although HMGN1 and HMGB1 function both as chromatin binding proteins and as alarmins, they are otherwise completely distinct proteins, unrelated in amino acid sequence. Two biological activities of HMGN1 can potentially be harnessed as antitumor activities. First, inside the nucleus, HMGN1 acts as a chromatin modifier to regulate chromatin structure, gene expression and post-translational modification of core histones, all of which are factors that affect DNA repair and tumor progression [3]. Second, HMGN1 is released by nonleukocytes such as epithelial cells in response to injurious agents, changes in intracellular calcium and inflammatory stimulants. When released by the cells, extracellular HMGN1 function as a Th1-polarizing alarmin that promotes the induction of innate and adaptive antitumor immune responses [4]. In the absence of nuclear HMGN1, cells become prone to mutagenic stimuli. Hmgn1 cells derived from HMGN1 knockout mice are hypersensitive to UV and ionizing irradiation, and show decreased capacity to repair DNA damage [5,6]. Consequently, Hmgn1 mice exhibit increased tumor formation in response to irradiation [7] or chemical carcinogens [8]. Even without treatment with exogenous DNA-damaging agents, Hmgn1 mice develop twice as many spontaneous tumors as their Hmgn1 littermates [7], supporting the notion that HMGN1 plays a role in DNA repair and the maintenance of genome stability. Given the requirement of multiple mutations in the course of cancer development [1,9], HMGN1 could potentially be used as a molecular target designed to counteract Harnessing the alarmin HMGN1 for anticancer therapy