| 摘要: | HMGA2 is located on chromosome 12q14.3, which is frequently amplified or subjected to chromosomalrearrangements found in human cancers. However, the detailed mechanismunderlying the HMGA2-dysregulated DNA damage response remains unclear. Herein we provide the first molecular and cellular evidence to suggest the direct involvement of HMGA2 in causing defects in NHEJ repair against DNA double-strand breaks (DSBs).Second, expression of HMGA2 results in spontaneous chromosome aberrations in WI-38 cells. Third, using real-time imaging in living cells,a sustained accumulation of DNA-PKcs at DSB sites in HMGA2-expressing cells receiving microirradiation was observed, resembling to observations found among DNA-PKcs mutants. In addition,HMGA2 significantly decreased overall HDAC activities, enhanced basal telomerase activities,and conveyed resistance to two different classes of telomerase inhibitors,TMPyP4,a G-quadruplex stabilizer,and GRN163L,an oligonucleotide targeting the active site in the template region of telomerase RNA (hTR), using telomeric repeat amplification protocol(TRAP)assays. Expression of HMGA2 rendered co-transfected hTERT-reporter activation in a dose-dependent manner in WI-38 cells. Moreover, observations on the reactivation of telomerase activity in non-transformed WI-38 cells transduced with lenti-HMGA2 and a positive correlation between the expression levels of HMGA2 and hTERT(p=0.01)from34 breast cancer patient samples further confirm a critical role for HMGA2 to induce hTERT expression .Lastly, increased HMGA2 expression correlates with unfavorable treatment outcome in breast cancer. Taken together, these results support a model in which the interplay between Ku70/80and HMGA2 interferes with NHEJ and telomere shortening and shed light on a novel role of HMGA2 in promoting genome instability. Clinically, the elevated expression of HMGA2 in a broad spectrum of cancers can be potentially utilized as a biomarker that reflects a lack of proper DNA damage response and telomere homeostasis and suggest a potential cancer therapeutics marker. |
