Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes

Abstract

LincRNA-p21 is a long noncoding RNA and a transcriptional target of p53 and HIF-1α. LincRNA-p21 regulates gene expression in cis and trans, mRNA translation, protein stability, the Warburg effect, and p53-dependent apoptosis and cell cycle arrest in doxorubicin-treated mouse embryo fibroblasts. p53 plays a key role in the response of skin keratinocytes to UVB-induced DNA damage by inducing cell cycle arrest and apoptosis. In skin cancer development, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. We hypothesized that lincRNA-p21 has a key functional role in UVB-induced apoptosis and/or cell cycle arrest in keratinocytes and loss of lincRNA-p21 function results in the evasion of apoptosis and/or cell cycle arrest. We observed that lincRNA-p21 transcripts are highly inducible by UVB in mouse and human keratinocytes in culture and in mouse skin in vivo. LincRNA-p21 is regulated at the transcriptional level in response to UVB, and the UVB induction of lincRNA-p21 in keratinocytes and in vivo in mouse epidermis is primarily through a p53-dependent pathway. Knockdown of lincRNA-p21 blocked UVB-induced apoptosis in mouse and human keratinocytes, and lincRNA-p21 was responsible for the majority of UVB-induced and p53-mediated apoptosis in keratinocytes. Knockdown of lincRNA-p21 had no effect on cell proliferation in untreated or UVB-treated keratinocytes. An early event in skin cancer is the mutation of a single p53 allele. We observed that a mutant p53+/R172H allele expressed in mouse epidermis (K5Cre+/tg;LSLp53+/R172H) showed a significant dominant-negative inhibitory effect on UVB-induced lincRNA-p21 transcription and apoptosis in epidermis. We conclude lincRNA-p21 is highly inducible by UVB and has a key role in triggering UVB-induced apoptotic death. We propose that the mutation of a single p53 allele provides a pro-oncogenic function early in skin cancer development through a dominant inhibitory effect on UVB-induced lincRNA-p21 expression and the subsequent evasion of UVB-induced apoptosis.

Expanding the p53 regulatory network: LncRNAs take up the challenge

“…Besides this initial finding in mouse cells, other studies supported the importance of lincRNA-p21 in regulating p53-mediated response in mouse and human models [38,39]. Notably, it has been reported that lincRNA-p21 maintains its role as mediator of p53 activity also in somatic reprograming of murine cells [40].…”

Heat stress: A risk factor for skin carcinogenesis

“…Interestingly, the high number of CPD keratinocytes that persisted in UVB plus heat-treated samples, suggests possible impairment of the DNA damage repair mechanisms. Normally, formation of CPDs induces p53-mediated cell cycle arrest and the activation of nucleotide excision repair (NER) mechanisms (Cheo et al, 1996;Hall et al, 2015).…”

Expression Profiles of Long Noncoding RNA in UVA-Induced Human Skin Fibroblasts

“…Expression levels of lnc-GKN2-1:1, lnc-CD1D-2:1, and lnc-SGCG-5:4 and ROS content were significantly increased after UVB irradiation [19]. Hall et al [20] reported that lincRNA-p21 was highly inducible by UVB and had a key role in triggering UVB-induced apoptotic death. Here, repeated UVA irradiation changed lncRNA expression in human skin fibroblasts.…”