SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells

• Published in: Oncogene 2019-08, Vol.38 (34), p.6196-6210
• Main Authors: Sun, Qiao-Yang, Ding, Ling-Wen, Johnson, Kara, Zhou, Siqin, Tyner, Jeffrey W., Yang, Henry, Doan, Ngan B., Said, Jonathan W., Xiao, Jin-Fen, Loh, Xin-Yi, Ran, Xue-Bin, Venkatachalam, Nachiyappan, Lao, Zhentang, Chen, Ye, Xu, Liang, Fan, Li-Fei, Chien, Wenwen, Lin, De-Chen, Koeffler, H. Phillip
• Format: Article
• Language: English
• Subjects: 38; 38/39; 38/61; 631/154/1435; 631/67/1059/2326; Animals; Apoptosis; Apoptosis - genetics; Bcl-2-Like Protein 11 - genetics; Bcl-2-Like Protein 11 - metabolism; BIM protein; Bortezomib; Breast; Breast cancer; Cancer; Cancer cells; Care and treatment; Cell Biology; Cell survival; Cell Survival - genetics; Cellular signal transduction; Drug resistance; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Genetic aspects; HEK293 Cells; Histone deacetylase; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; MAP kinase; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; MEK inhibitors; Mice; Mice, SCID; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncology; Phenotypes; Proteasome inhibitors; Signal transduction; SOXF Transcription Factors - genetics; SOXF Transcription Factors - physiology; Tumor Cells, Cultured
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0865-8

Apoptosis of cancer cells occurs by a complex gene regulatory network. Here we showed that SOX7 was significantly downregulated in different cancer types, especially in lung and breast cancers. Low expression of SOX7 was associated with advantage stage of cancer with shorter overall survival. Cancer cells with loss of SOX7 promoted cell survival and colony formation, suppressed cellular apoptosis and produced a drug resistant phenotype against a variety of chemo/targeting therapeutic agents. Mechanistically, SOX7 induced cellular apoptosis through upregulation of genes associated with both P38 and apoptotic signaling pathway, as well as preventing the proteasome mediated degradation of pro-apoptotic protein BIM. Treatment of either a proteasome inhibitor MG132 or bortezomib, or with a p-ERK/MEK inhibitor U0126 attenuate the SOX7 promoted BIM degradation. We identified Panobinostat, an FDA approved pan-HDAC inhibitor, could elevate and restore SOX7 expression in SOX7 silenced lung cancer cells. Taken together, these data revealed an unappreciated role of SOX7 in regulation of cellular apoptosis through control of MAPK/ERK-BIM signaling.