Gene expression data from parental HeLa and Dickkopf-1 (Dkk1) knockout HeLa cells after Cisplatin treatment. Gene expression data from parental HeLa and Dickkopf-1 (Dkk1) knockout HeLa cells after Cisplatin treatment

Infection with oncogenic human papillomavirus (HPV) is a major cause for the development of cervical cancer, which is mainly driven by the expression of the HPV E6 and E7 oncoproteins. We uncovered that the concentration levels of the putative tumor suppressor Dickkopf-1 (Dkk1) are restricted in cervical cancer cells by HPV E6 expression due to the E6-mediated proteolytic degradation of p53, which is a transcriptional regulator of Dkk1. Moreover, we found that Dkk1 is critically involved in the pro-apoptotic Cisplatin response of these cells, as Dkk1 repression was associated with an increased resistance towards the chemotherapeutic compound. This could be of high relevance for cervical cancer treatments, which usually involve Cisplatin for standard care. Although Dkk1 is a major antagonist of the canonical Wnt signaling, the differential response towards Cisplatin observed in Dkk1-depleted cells was not associated to an activation of this pathway. To elucidate alternative underlying mechanisms, we performed Affymetrix Gene Expression analyses comparing the transcriptome of Cisplatin-treated parental HeLa to CRISPR/Cas9-generated Dkk1 knockout (KO) HeLa cells. These revealed that Dkk1 depletion is linked to an impairment of the pro-apoptotic JNK/AP-1 pathway in cervical cancer cells, suggesting that Dkk1 drives Cisplatin-mediated apoptosis via activation of this signaling hub. Overall design: Parental HeLa (HeLa WT) and Dkk1 KO HeLa cells were treated for 16 h with 10 µM Cisplatin or were left untreated. After extracting total RNA from the samples, cRNA was generated and hybridized on Affymetrix® GeneChips. All conditions were performed in three biological replicates.