Abstract
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an important cofactor in the p53-mediated DNA damage response pathway upon ionizing radiation (IR) and exerts anti-apoptotic effects also independent of p53 pathway activation. Furthermore, hnRNP K is overexpressed in various neoplasms including malignant melanoma (MM). Here, we investigate the role of hnRNP K in the radioresistance of MM cells. Our results show cytoplasmic expression of hnRNP K in human MM surgical specimens, but not in benign nevi, and a quick dose- and time-dependent upregulation in response to IR accompanied by cytoplasmic redistribution of the protein in the IPC-298 cellular tumor model carrying an activating NRAS mutation (p.Q61L). SiRNA-based knockdown of hnRNP K induced a delayed decline in γH2AX/53BP1-positive DNA repair foci upon IR. Pharmacological interference with MAPK signaling abrogated ERK phosphorylation, diminished cellular hnRNP K levels, impaired γH2AX/53BP1-foci repair and proliferative capability and increased apoptosis comparable to the observed hnRNP K knockdown phenotype in IPC-298 cells. Our results indicate that pharmacological interference with MAPK signaling increases vulnerability of NRAS-mutant malignant melanoma cells to ionizing radiation along with downregulation of endogenous hnRNP K and point towards a possible use for combined MEK inhibition and localized radiation therapy of MM in the NRAS-mutant setting where BRAF inhibitors offer no clinical benefit.
Highlights
Heterogeneous nuclear ribonucleoprotein K is an important cofactor in the p53-mediated DNA damage response pathway upon ionizing radiation (IR) and exerts anti-apoptotic effects independent of p53 pathway activation
There was no significant difference in nuclear Heterogeneous nuclear ribonucleoprotein K (hnRNP K) staining between diagnostic groups; in contrast, cytoplasmic hnRNP K positivity was only detected in MM and MM metastases (25% of cases), but not in benign nevi (Fig. 1B)
These results indicate a positive correlation between mitogen-activated protein kinase (MAPK) signaling activity and hnRNP K expression levels in Neuroblastoma rat sarcoma (NRAS)-mutant IPC-298 cells
Summary
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an important cofactor in the p53-mediated DNA damage response pathway upon ionizing radiation (IR) and exerts anti-apoptotic effects independent of p53 pathway activation. The presence of heterogeneous nuclear ribonucleoprotein K www.impactjournals.com/oncotarget (hnRNP K) has been described to be essential for p53-mediated effects following DNA damage [5]. Three K-homology (KH) domains enable hnRNP K to bind to poly(C)-rich DNA and pre-mRNA sequences; the protein is closely involved in regulating gene expression and posttranscriptional mRNA modifications, including mRNA maturation and translation. The pivotal functions of hnRNP K for cell survival and homeostasis are regulated by a fine adjustment of its subcellular (nuclear or cytoplasmic) localization, phosphorylation state and protein-protein interactions [7,8,9]. HnRNP K is a key player in the cellular response to DNA damage and inhibition of apoptosis
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