Theranostics 2020; 10(22):10001-10015. doi:10.7150/thno.47491 This issue Cite

Research Paper

Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression

Che-Chung Lin1, I-Ying Kuo1, Li-Ting Wu1, Wen-Hui Kuan1, Sheng-You Liao2, Jayu Jen2, You-En Yang1, Cheng-Wei Tang1, Yi-Rong Chen3, Yi-Ching Wang1,2✉

1. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
3. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 35053, Taiwan.

Citation:
Lin CC, Kuo IY, Wu LT, Kuan WH, Liao SY, Jen J, Yang YE, Tang CW, Chen YR, Wang YC. Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics 2020; 10(22):10001-10015. doi:10.7150/thno.47491. https://www.thno.org/v10p10001.htm
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Abstract

Graphic abstract

Angiogenesis enhances cancer metastasis and progression, however, the roles of transcription regulation in angiogenesis are not fully defined. ZNF322A is an oncogenic zinc-finger transcription factor. Here, we demonstrate a new mechanism of Kras mutation-driven ZNF322A transcriptional activation and elucidate the interplay between ZNF322A and its upstream transcriptional regulators and downstream transcriptional targets in promoting neo-angiogenesis.

Methods: Luciferase activity, RT-qPCR and ChIP-qPCR assays were used to examine transcription regulation in cell models. In vitro and in vivo angiogenesis assays were conducted. Immunohistochemistry, Kaplan-Meier method and multivariate Cox regression assays were performed to examine the clinical correlation in tumor specimens from lung cancer patients.

Results: We validated that Yin Yang 1 (YY1) upregulated ZNF322A expression through targeting its promoter in the context of Kras mutation. Reconstitution experiments by knocking down YY1 under KrasG13V activation decreased KrasG13V-promoted cancer cell migration, proliferation and ZNF322A promoter activity. Knockdown of YY1 or ZNF322A attenuated angiogenesis in vitro and in vivo. Notably, we validated that ZNF322A upregulated the expression of sonic hedgehog (Shh) gene which encodes a secreted factor that activates pro-angiogenic responses in endothelial cells. Clinically, ZNF322A protein expression positively correlated with Shh and CD31, an endothelial cell marker, in 133 lung cancer patient samples determined using immunohistochemistry analysis. Notably, patients with concordantly high expression of ZNF322A, Shh and CD31 correlated with poor prognosis.

Conclusions: These findings highlight the mechanism by which dysregulation of Kras/YY1/ZNF322/Shh transcriptional axis enhances neo-angiogenesis and cancer progression in lung cancer. Therapeutic strategies that target Kras/YY1/ZNF322A/Shh signaling axis may provide new insight on targeted therapy for lung cancer patients.

Keywords: Lung cancer, Kras, Shh, transcription, angiogenesis


Citation styles

APA
Lin, C.C., Kuo, I.Y., Wu, L.T., Kuan, W.H., Liao, S.Y., Jen, J., Yang, Y.E., Tang, C.W., Chen, Y.R., Wang, Y.C. (2020). Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics, 10(22), 10001-10015. https://doi.org/10.7150/thno.47491.

ACS
Lin, C.C.; Kuo, I.Y.; Wu, L.T.; Kuan, W.H.; Liao, S.Y.; Jen, J.; Yang, Y.E.; Tang, C.W.; Chen, Y.R.; Wang, Y.C. Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics 2020, 10 (22), 10001-10015. DOI: 10.7150/thno.47491.

NLM
Lin CC, Kuo IY, Wu LT, Kuan WH, Liao SY, Jen J, Yang YE, Tang CW, Chen YR, Wang YC. Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics 2020; 10(22):10001-10015. doi:10.7150/thno.47491. https://www.thno.org/v10p10001.htm

CSE
Lin CC, Kuo IY, Wu LT, Kuan WH, Liao SY, Jen J, Yang YE, Tang CW, Chen YR, Wang YC. 2020. Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics. 10(22):10001-10015.

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