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.

Figure 1.

A. Pleiotropic roles of HMGB1 in cells. HMGB1 has been found to be involved in DNA repair, chronic inflammation, immune responses, autophagy, DNA damage responses etc. Please see text for detailed description. B. Expression levels of HMGB mRNAs are higher in cancerous tissues when compared to the normal surrounding tissues as measured by Illumina RNA Seq V2 of cancer patient samples from 158 studies. The fold increase in expression levels as a function of mRNA in cancer samples are plotted in an increasing order of median values of the expression level. Samples with mutations are also identified in the same plot. The copy number and expression levels are not always linearly correlated. A gain in copy number can also be accompanied by missense mutations or small truncating mutations, resulting in lower expression levels in those particular samples. a, HMGB1 expression levels and copy number alterations data from 42,049 samples. The HMGB1 gene was mutated in 263 patients. b, HMGB2 expression levels and copy number alterations from 42,049 samples. The HMGB2 gene was mutated in 285 of the queried patients. c, HMGB3 expression levels and copy number alterations from the 42,049 samples. The HMGB3 gene is altered in 351 of the queried patients. The data was procured, analyzed, and the graphs were prepared using cBioPortal. The copy number level per gene was derived from copy number analysis algorithms. Amplification = many additional gene copies, local; Gain = a few additional copies, broad; Diploid = two complete sets of chromosomes; Shallow deletion = possible heterozygous deletion; Deep deletion = possible homozygous deletion. CNA = Copy Number Alteration; GBM = Glioblastoma; AML = Acute Myeloid Leukemia; DLBC = Diffuse large B cell lymphoma; Lung Squ = Lung squamous cell carcinoma; Testicular GC = Testicular Germ Cell. C. HMGB mRNAs are expressed differentially in different ovarian serous cystadenocarcinoma patients. Heat maps representing the mRNA levels from 398 patient samples were generated from the TCGA Next-Generation Clustered Heat Map (NG-CHM) Compendium (https://bioinformatics.mdanderson.org/TCGA/NGCHMPortal/).