HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

Abstract

DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxiatelangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage-and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

Chaperoning HMGA2 Protein Protects Stalled Replication Forks in Stem and Cancer Cells

“…We employed small interfering RNA (siRNA)-mediated HMGA2 KD and confirmed a general protective function exerted by endogenous HMGA2 against fork cleavage, as indicated by a significant increase in the amount of fragmented DNA seen in the comet tails when endogenous HMGA2 levels were reduced by about 50% ( Figure 3D). Together, these results are in excellent agreement with previous findings that revealed significant protective effects of HMGA2 against drug-induced DNA damage in mouse embryonic fibroblasts and in human cancer cells expressing exogenous HMGA2 (Palmieri et al, 2011;Summer et al, 2009).…”

“…In addition, the lack of HMGA genes does not alter cell growth, indicating that HMGA proteins are not essential factors for DNA replication (Beitzel and Bushman, 2003;Palmieri et al, 2011). However, when forks are arrested, the presence of HMGA2 protects forks from nucleolytic collapse.…”

ATM-Mediated Phosphorylation of Cortactin Involved in Actin Polymerization Promotes Breast Cancer Cells Migration and Invasion

“…However, other recent research suggested that ATM is also involved in many other cancer signaling pathways other than DNA damage response, which relates to chemoresistance, radioresistance, metastasis, cell growth and proliferation. Chemoresistance may be caused by DNA damage-independent ATM signaling via overexpression of HMGA proteins [42]. Oxidized ATM signaling, supports breast tumor metastasis through the regulation of IL-8 [36].…”

HMGA1 expression in human gliomas and its correlation with tumor proliferation, invasion and angiogenesis

“…Overexpression of HMGA1 can significantly upregulate a number of genes involved in cell cycle regulation, signal transduction, neoplastic transformation, and tumor progression in various systems, including CLK-1, cdc25A, cdc25B, cyclin C, JNK2, and p38 MAPK [38]. HMGA1 inhibits the function of p53 family members in thyroid cancer cells, increases the expression of oncogenic miR-222 in lung cancer cells, enhances cancer cell resistance to genotoxic agents, enhances epithelial-mesenchymal transition, and promotes tumor progression in breast cancer cells [25,[38][39][40]. Recent study has shown HMGA1 upregulation to be associated with survival in pancreatic ductal adenocarcinoma whereas downregulation of HMGA1 has enhanced gemcitabine chemosensitivity for suppressing growth of tumor cells [26,41,42].…”