CBP-mediated Wnt3a/β-catenin signaling promotes cervical oncogenesis initiated by Piwil2

Dingqing Feng, Keqin Yan, Haiyan Liang, Jing Liang, Wenhui Wang, Huan Yu, Ying Zhou, Weidong Zhao, Zhongjun Dong, Bin Ling
Neoplasia: An International Journal for Oncology Research 2020 November 12, 23 (1): 1-11
Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma. Blocking the β-catenin and CREB binding protein interaction with ICG-001 significantly downregulated the reprogramming factors c-Myc, Nanog, Oct4, Sox2, and Klf4, thus leading to cell differentiation and preventing tumorigenicity in Piwil2-overexpressing HaCaT cells. Similarly, Piwil2 also critically regulated the canonical Wnt signaling pathway in cervical cancer. We further demonstrated that ICG-001 increased cisplatin sensitivity and significantly suppressed tumor growth of cervical cancer alone or in combination with cisplatin both in vitro and in vivo. The β-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.

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