Schlafen 12 Is Prognostically Favorable and Reduces C-Myc and Proliferation in Lung Adenocarcinoma but Not in Lung Squamous Cell Carcinoma

SIMPLE SUMMARY: Different subtypes of lung cancer respond differently to treatment. To understand the signaling pathways that dictate the aggressive behavior of lung adenocarcinoma vs. lung squamous cell carcinoma, we performed a survival analysis that demonstrated that the protein Schlafen 12 correlates with better survival in patients with lung adenocarcinoma but not patients with lung squamous cell carcinoma, indicating specificity of the effect of the SLFN12 pathway in lung cancer subtypes. We investigated this specific effect by confirming the ability of Schlafen 12 to reduce cell proliferation of lung adenocarcinoma cells in vitro but not that of lung squamous cell carcinoma. Moreover, we demonstrated that Schlafen 12 acts through translational inhibition of c-myc protein in lung adenocarcinoma cells. The ability to delineate the exact signaling pathways that modulate each lung cancer subtype’s aggressive behavior will help in the future development of precision medicine to target this challenging disease. ABSTRACT: Schlafen 12 (SLFN12) is an intermediate human Schlafen that induces differentiation in enterocytes, prostate, and breast cancer. We hypothesized that SLFN12 influences lung cancer biology. We investigated survival differences in high versus low SLFN12-expressing tumors in two databases. We then adenovirally overexpressed SLFN12 (AdSLFN12) in HCC827, H23, and H1975 cells to model lung adenocarcinoma (LUAD), and in H2170 and HTB-182 cells representing lung squamous cell carcinoma (LUSC). We analyzed proliferation using a colorimetric assay, mRNA expression by RT-qPCR, and protein by Western blot. To further explore the functional relevance of SLFN12, we correlated SLFN12 with seventeen functional oncogenic gene signatures in human tumors. Low tumoral SLFN12 expression predicted worse survival in LUAD patients, but not in LUSC. AdSLFN12 modulated expression of SCGB1A1, SFTPC, HOPX, CK-5, CDH1, and P63 in a complex fashion in these cells. AdSLFN12 reduced proliferation in all LUAD cell lines, but not in LUSC cells. SLFN12 expression inversely correlated with expression of a myc-associated gene signature in LUAD, but not LUSC tumors. SLFN12 overexpression reduced c-myc protein in LUAD cell lines but not in LUSC, by inhibiting c-myc translation. Our results suggest SLFN12 improves prognosis in LUAD in part via a c-myc-dependent slowing of proliferation.