Abstract
Long noncoding RNAs (LncRNAs), including MALAT1, are critical regulators of tumor development. However, the roles and molecular mechanisms of LncRNAs in cutaneous squamous cell carcinoma (cSCC) remain underexplored. In this study, functional studies using in vitro cellular and in vivo xenograft models confirmed the pro-carcinogenic roles of MALAT1 in cSCC. Further, MALAT1 was identified to regulate epidermal growth factor receptor (EGFR) protein expression but did not affect EGFR mRNA expression. Transcriptomic sequencing identified kinectin 1 (KTN1) as the key mediator for MALAT1 regulation of EGFR. Mechanistic study revealed that MALAT1 interacts with c-MYC to form a complex and directly binds to the promoter region of KTN1 gene and enhances its transactivation to positively regulate EGFR protein expression. Our findings, therefore, establish a novel c-MYC-assisted MALAT1-KTN1-EGFR axis, which contributes to cSCC development and may serve as novel target for therapeutic intervention.
Highlights
Cutaneous squamous cell carcinoma represents the second most common cancer worldwide with an annual accidence over one million individuals [1, 2]. cSCC most frequently develops in skin that receives chronic sun exposure and generates ultraviolet (UV)-induced DNA damage in epidermal keratinocytes, leading to theThese authors contributed : Ying Zhang, Lin GaoEdited by R
Quantitative reverse transcription PCR detection indicated that Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is stably and markedly higher expressed in all cSCC cell lines with similar folds compared with other Long noncoding RNAs (LncRNAs), which may indicate its tightly relationship with cSCC development (Fig. 1a and Supplementary Fig. S1b–j)
Serving as an activator of the MAPK, PI3K, and KRAS pathways, epidermal growth factor receptor (EGFR) contributes to proliferation and metastasis of cancer cells and can be activated upon UV exposure [19]
Summary
Cutaneous squamous cell carcinoma (cSCC) represents the second most common cancer worldwide with an annual accidence over one million individuals [1, 2]. cSCC most frequently develops in skin that receives chronic sun exposure and generates ultraviolet (UV)-induced DNA damage in epidermal keratinocytes, leading to the. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a 8000 nt-long single-exon noncoding transcript highly expressed in nucleus, is upregulated in many solid cancers and regulates alternative splicing or transcription to promote cancer progression, metastasis, and recurrence [7,8,9]. The migration and metastasis capacity of tumor cells was markedly compromised in MALAT1deficient cells owing to the decreased expression of proliferation, invasiveness, and metastasis-related genes [10]. MALAT1 physically interacts with c-MYC, promotes its chromatin recruitment, and binds directly to the KTN1 promoter region to transactivate KTN1 expression for enhancing EGFR protein expression. In vivo and in vitro identification of this novel MALAT1-KTN1EGFR axis deepens our understanding of the pivotal roles of LncRNAs in cSCC progression and provides new target for anti-cancer intervention
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