Abstract
Small cell lung cancer (SCLC) is a highly malignant form of cancer, which originates from primitive neuroendocrine cells in the lung. SCLC cells express several autocrine neurotransmitters/neuropeptides and their respective receptors. Expression of these neuronal markers is frequently regulated by RE1-silencing transcription factor (REST). In SCLC cells, an SCLC-specific isoform of REST (sREST) is highly expressed, whereas REST expression is undetectable, suggesting that the expression of sREST correlates with the pathogenesis of SCLC. Expression of sREST, which is derived through alternative splicing of REST, is abnormally regulated in SCLC cells, but the mechanism is unknown. Most recently, nSR100 (SRRM4) was described as an activator of REST alternative splicing. We now show that nSR100 is highly expressed in SCLC cells correlating with high sREST and low REST expression. Adhesion to the extracellular matrix (ECM) is thought to enhance tumorigenicity and confer resistance to apoptosis. Interestingly, nSR100 expression is enhanced in cells grown with ECM. Overexpression of REST caused repression of sREST and nSR100, the latter containing RE1 element controlled by REST. Culturing the SCLC cell line NCI-N417 cells with ECM also upregulated RE1-containing gene, the voltage-gated calcium channel subunit. Inhibition of the PI3K/Akt/mTOR pathway by LY294002 induced nSR100 expression, whereas the specific MEK/ERK inhibitor U0126 inhibited nSR100 expression. Repressing nSR100 by siRNA effectively repressed sREST, and conversely increased REST in NCI-N417 cells. Taken together, this report clarifies the ECM-dependent signaling pathway that impacts nSR100 expression and its regulation of alternative splicing in SCLC. The splicing factor nSR100 may be novel SCLC-specific biomarker, as well as a therapeutic target.
Highlights
Lung cancer is the leading cause of cancer-related death in the world, which includes small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC; ref. 1)
Results and Discussion nSR100 is abnormally expressed in Small cell lung cancer (SCLC) cells SCLC is thought to originate from primitive neuroendocrine cells in the lung [2] and progresses aggressively fast
SCLC expresses various autocrine neuropeptides, transmitters and their corresponding receptors, as well as several neuronal markers, which are transcriptionally regulated by the transcription factor RE1-silencing transcription factor (REST)
Summary
Lung cancer is the leading cause of cancer-related death in the world, which includes small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC; ref. 1). Abnormal expression of REST has been reported to correlate with several forms of cancer [9, 10]. Alternative Splicing of REST/NRSF in SCLC Cells an RE1 element which include genes that encode proteins of fundamental importance for cell function. These include signaling proteins, adhesion molecules, synaptic vesicle proteins, neuronal receptors, and channel proteins [13, 14]. The REST gene is itself regulated by alternative splicing generating isoforms containing four, five, and nine Nterminal zinc finger domains. In human SCLC, sREST has homology to a mouse neuron-specific REST isoform, REST4, which contains the five Nterminal zinc finger domains [18]. This study provides a new insight into the role of nSR100 in the expression of sREST, possibly in the pathogenesis of SCLC
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