The incidence of lung diseases and cancer caused by cigarette smoke is increasing. The molecular mechanisms of gene regulation induced by cigarette smoke that ultimately lead to cancer remain unclear. This report describes a novel long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) both in vitro and in vivo and is elevated in numerous lung cancer cell lines. We have termed this lncRNA the smoke and cancer-associated lncRNA-1 (SCAL1). This lncRNA is located in chromosome 5, and initial sequencing analysis reveals a transcript with four exons and three introns. The expression of SCAL1 is regulated transcriptionally by nuclear factor erythroid 2-related factor (NRF2), as determined by the small, interfering RNA (siRNA) knockdown of NRF2 and kelch-like ECH-associated protein 1 (KEAP1). A nuclear factor erythroid-derived 2 (NF-E2) motif was identified in the promoter region that shows binding to NRF2 after its activation. Functionally, the siRNA knockdown of SCAL1 in human bronchial epithelial cells shows a significant potentiation of cytotoxicity induced by CSE in vitro. Altogether, these results identify a novel and intriguing new noncoding RNA that may act downstream of NRF2 to regulate gene expression and mediate oxidative stress protection in airway epithelial cells.Keywords: lincRNA; cancer; smoke; NRF2; epigenetics Recent advances in sequencing technology have revealed that significant numbers of noncoding RNAs are expressed and have significant functions in regulating gene expression. Noncoding RNAs have been classified according to size as either microRNAs (less than 200 base pairs) to long noncoding RNAs (greater than 200 base pairs; lncRNAs). LncRNAs have been further subdivided, based on their location relative to coding genes. Native antisense transcripts overlap with coding genes, intronic lncRNAs are expressed from the introns of coding genes, and long intergenic noncoding RNAs (lincRNAs) are found in the genome between coding genes (1). Unlike micro-RNAs, lncRNAs are much less well characterized, and how they function in biology and gene regulation remains an active area of investigation.Using gain and loss of function approaches, the function of individual lncRNAs are gradually being elucidated. X-inactive specific transcript (XIST), one of the earliest identified lncRNAs, plays an essential role in sex-specific imprinting by epigenetically silencing one of the two X chromosomes in female zygotes through the recruitment of polycomb repressor complexes (PRC2) (2). Other lncRNAs, such as HOX antisense intergenic RNA (HOTAIR) and P21-associated ncRNA DNA damage activated (PANDA), have also been found to regulate the chromatin state through their effects on the PRC2 complex (3, 4). Beyond its novelty in regulating important biological functions through epigenetic mechanisms, emerging evidence suggests that lncRNAs are associated with and may cause diseases such as cancer. Abnormal expressions of lncRNAs have been associated with cancers of the lung and breast (5, 6). Specific lnc...

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