HMGA1 Modulates Gene Transcription Sustaining a Tumor Signalling Pathway Acting on the Epigenetic Status of Triple-Negative Breast Cancer Cells

Abstract

Chromatin accessibility plays a critical factor in regulating gene expression in cancer cells. Several factors, including the High Mobility Group A (HMGA) family members, are known to participate directly in chromatin relaxation and transcriptional activation. The HMGA1 oncogene encodes an architectural chromatin transcription factor that alters DNA structure and interacts with transcription factors favouring their landing onto transcription regulatory sequences. Here, we provide evidence of an additional mechanism exploited by HMGA1 to modulate transcription. We demonstrate that, in a triple-negative breast cancer cellular model, HMGA1 sustains the action of epigenetic modifiers and in particular it positively influences both histone H3S10 phosphorylation by ribosomal protein S6 kinase alpha-3 (RSK2) and histone H2BK5 acetylation by CREB-binding protein (CBP). HMGA1, RSK2, and CBP control the expression of a set of genes involved in tumor progression and epithelial to mesenchymal transition. These results suggest that HMGA1 has an effect on the epigenetic status of cancer cells and that it could be exploited as a responsiveness predictor for epigenetic therapies in triple-negative breast cancers.

Long noncoding RNA LINC00963 promotes breast cancer progression by functioning as a molecular sponge for microRNA-625 and thereby upregulating HMGA1

“…HMGA1, a member of the HMGA protein family, regulates chromatin structure by directly binding to the A/T-rich DNA sequences located in the promoter and enhancer regions of multiple human genes [42]. HMGA1 exerts a crucial effect on the malignancy of breast cancer and is implicated in the regulation of various malignant characteristics [43][44][45]. Our current study revealed that the depletion of LINC00963 restrains the aggressiveness of breast cancer cells in vitro and in vivo; these influences turned out to be mediated by decreased sponging of miR-625 and consequent HMGA1 upregulation.…”

Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

“…Interestingly, the cAMP response element binding protein (CREB) binding protein gene (CREBBP) was downregulated following acute EVOO intervention, in both normal weight and obese individuals [175]. CREBBP catalyzes the acetylation of HMGA1 [177] and histone H2B [178], exerting a modulatory effect on HMGA1-linked transcriptional programs in breast cancer cells. Also, given that one of the genes modulated by EVOO is the argonaute RISC catalytic component 2 (AGO2), a master regulator of microRNAs biogenesis and protein synthesis, it is unsurprising that microRNA expression could be also affected by EVOO, with pleiotropic consequences on IR, inflammation and tumorigenesis [175].…”

HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel

“…Transcriptomic approaches have demonstrated that HMGA1 controls a gene network involved in critical processes in BC such as epithelial-to-mesenchymal transition (EMT), stemness, cell proliferation, migration, and invasion [ 19 – 22 ]. In addition, data suggest that HMGA1 might promote chromatin relaxation through a histone H1-mediated mechanism, impacting nuclear stiffness and thus favouring the invasiveness of cancer cells [ 23 ].…”