Theranostics 2020; 10(1):265-280. doi:10.7150/thno.36045

Research Paper

Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer

Xuan Deng1*, Sihan Li2*, Fanyang Kong3, Haoyu Ruan1, Xiao Xu1, Xinju Zhang1, Zhiyuan Wu1, Lin Zhang4, Ying Xu5, Hong Yuan6, Haixia Peng5✉, Da Yang2✉, Ming Guan1✉

1. Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China;
2. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA;
3. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 222300, China;
4. UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA;
5. Digestive Endoscopy Center, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200050, China;
6. Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
*These authors contributed equally to this article.

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Citation:
Deng X, Li S, Kong F, Ruan H, Xu X, Zhang X, Wu Z, Zhang L, Xu Y, Yuan H, Peng H, Yang D, Guan M. Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer. Theranostics 2020; 10(1):265-280. doi:10.7150/thno.36045. Available from http://www.thno.org/v10p0265.htm

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Abstract

We identified a novel long noncoding RNA (lncRNA) upregulated in colorectal cancer (CRC). We elucidated its role and clinical significance in CRC carcinogenesis.

Methods: LncRNA candidates were identified using TCGA database. LncRNA expression profiles were studied by qRT-PCR and microarray in paired tumor and normal tissues. The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. The mechanisms of lncRNA function and regulation in CRC were examined using molecular biological methods.

Results: We identified a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further in vitro and in vivo models demonstrated that PiHL was crucial in maintaining cell proliferation and inducing 5-FU chemoresistance through a p53-dependent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can directly bind to PiHL promoter and regulating its expression.

Conclusion: Our study illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and chemoresistance. PiHL plays an oncogenic role in CRC carcinogenesis and is an independent prognostic factor as well as a potential therapeutic target for CRC patients.

Keywords: Long noncoding RNA, Colorectal cancer, p53