The Small Cell Lung Cancer-Specific Isoform of RE1-Silencing Transcription Factor (REST) Is Regulated By Neural-Specific Ser/Arg Repeat-Related Protein of 100 kDa (nSR100)

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.

Interleukin‐6 induces neuroendocrine differentiation (NED) through suppression of RE‐1 silencing transcription factor (REST)

“…REST has been attributed a tumor suppressor function in breast cancer, and its expression is reduced with aggressiveness in breast cancer . Interestingly, a SCLC‐specific isoform of REST, which antagonizes REST‐mediated neuroendocrine gene expression, promoted tumor aggressiveness and neuronal phenotype in SCLCs . In colon cancer, the loss of REST expression confers a survival benefit during the progression of tumor cells .…”

Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer

“…Furthermore, our studies have reported that this reprogrammed RNA splicing signature is unique to NEPC patient tumors, PDX models, and cell models, indicating a clear variance in the phenotype of NEPC and AdPC tumors . The SRRM4‐driven t‐NEPC‐specific reprogramming of the transcriptome modifies anti‐apoptotic factors (eg, Bif‐1), epigenetic modifiers (eg, MEAF6‐1), and transcriptional regulators (eg, REST, FOXA1) that are important for regulating cell survival, proliferation and tumorigenesis, and neural differentiation, respectively . Together, these studies propose a model in which SRRM4 drives t‐NEPC development through alternative splicing of downstream genes …”

Insights into Novel Prognostic and Possible Predictive Biomarkers of Lung Neuroendocrine Tumors

“…This pathway is implicated in tumorextracellular matrix interactions that promote tumor proliferation. Preclinical studies with small-interfering RNAs have demonstrated encouraging results in suppressing sREST and restoring the REST level (81).…”