Targeting Chromosomal Architectural HMGB Proteins Could Be the Next Frontier in Cancer Therapy

Abstract

Chromatin-associated architectural proteins are part of a fundamental support system for cellular DNA-dependent processes and can maintain/modulate the efficiency of DNA replication, transcription, and DNA repair. Interestingly, prognostic outcomes of many cancer types have been linked with the expression levels of several of these architectural proteins. The High Mobility Group Box (HMGB) architectural protein family has been well studied in this regard. The differential expression levels of HMGB proteins and/or mRNAs and their implications in cancer etiology and prognosis present the potential of novel targets that can be explored to increase the efficacy of existing cancer therapies. HMGB1, the most studied member of the HMGB protein family, has pleiotropic roles in cells including an association with nucleotide excision repair, base excision repair, mismatch repair, and DNA double-strand break repair. Moreover, the HMGB proteins have been identified in regulating DNA damage responses and cell survival following treatment with DNA-damaging agents, and as such, may play roles in modulating the efficacy of chemotherapeutic drugs by modulating DNA repair pathways. Here, we discuss the functions of HMGB proteins in DNA damage processing, and their potential roles in cancer etiology, prognosis and therapeutics.

Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

“…The latter explanation may also be true for etoposide-treated hESCs [ 25 ]. Higher telomerase activity in the etoposide-treated HMGB2 KD hESCs (relative to control treated cells) may confirm the reported involvement of HMGB proteins in the DNA damage response [ 6 ]. Thus, enhanced telomerase activation in etoposide-treated HMGB2 KD hESCs may reflect augmented DNA damage response in these cells due to the absence of HMGB2 as a DNA damage protective protein.…”

“…Our findings on the distinct roles of HMGB1 and HMGB2 in the modulation of telomerase activity in etoposide-treated cells could be of interest for developing strategies for augmenting the efficacy of anticancer drugs [ 6 ]. It remains to be established whether the reported distinct impact of HMGB KD on the efficacy of anticancer drugs ([ 6 ] and refs. therein and in this paper) is correlated with HMGB-dependent changes in the cellular activity of telomerase.…”

“…hESCs are highly sensitive to DNA-damaging agents, which induce DNA repair mechanisms following genomic insult [ 3 ]. In eukaryotic cells, gene activation or repression (and, consequently, the execution of the differentiation program) is highly influenced by the structure of the chromosomal DNA, which is associated with histones and nonhistone HMG proteins, in particular, the HMGB-type proteins [ 4 , 5 , 6 ]. The majority of HMGB research has focused on the evolutionarily highly conserved HMGB1 and HMGB2 proteins, which are detectable at a high level in all types of embryonic and adult cells [ 7 , 8 ].…”

HMGB1 in inflammation and cancer

“…Loss of HMGB1 results in the instability of genome and leads to tumorigenesis. Thus, the roles of HMGB1 in regulation of DNA damage repair and cancer etiology indicate that targeting chromosomal architectural HMGB1 may provide a new perspective for cancer therapy [16]. HMGB1 located in the cytosol or mitochondria may bind to autophagy associated genes like Beclin 1 to regulate cell autophagy and mitophagy.…”

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…HMGB1 silencing was shown to inhibit autophagy and to increase asbestos-induced mesothelial cell death, thereby decreasing asbestos induced transformation ( 4 ) ( Figure 1 ). The importance of HMGB1 in cancerous transformation was also studied in a mouse mesothelioma model, where the investigators demonstrated that inhibition of HMGB1 binding to its receptors led to decreased tumor growth ( 5 , 6 ) again pointing out the importance of this mediator in MPM progression. In addition, serum concentrations of HMGB1 are also significantly higher in mesothelioma patients compared to healthy controls, indicating its significance in tumor development ( 7 ).…”