Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC).
The tumor suppressor LKB1 (STK11) is a cytoplasmic/nuclear serine/threonine kinase, defects in which cause Peutz-Jeghers syndrome (PJS) in humans and animals. Recent studies showed that loss of function of LKB1 is associated with sporadic forms of lung, pancreatic, and ovarian cancer. In cancer cells, LKB1 is inactivated by two mechanisms: mutations in its central kinase domain or complete loss of LKB1 expression. Inactivation of LKB1 is associated with progression of PJS and transformation of benign polyps into malignant tumors. This study examines the effect of LKB1 on regulation of STAT3 and expression of transcriptional targets of STAT3. The results show that LKB1 inhibits rearranged in transformation (RET)/papillary thyroid carcinoma (PTC)-dependent activation of signal transducer and activator of transcription 3 (STAT3), which is mediated by phosphorylation of STAT3 tyrosine 705 by RET/PTC. Suppression of STAT3 transactivation by LKB1 requires the kinase domain but not the kinase activity of LKB1. The centrally located kinase domain of LKB1 is an approximately 260-amino-acid region that binds to the linker domain of STAT3. Chromatin immunoprecipitation studies indicate that expression of LKB1 reduces the binding of STAT3 to its target promoters and suppresses STAT3-mediated expression of Cyclin D1, VEGF, and Bcl-xL. Knockdown of LKB1 by specific small interfering RNA led to an increase in STAT3 transactivation activity and promoted cell proliferation in the presence of RET/PTC. Thus, this study suggests that LKB1 suppresses tumor growth by inhibiting RET/PTC-dependent activation of oncogenic STAT3.
Kim
Dong Wook
DW
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Department of Pathology, Chungnam National University School of Medicine, Daejeon 301-721, Korea.
Chung
Hyo Kyun
HK
Park
Ki Cheol
KC
Hwang
Jung Hwan
JH
Jo
Young Suk
YS
Chung
Jongkyeong
J
Kalvakolanu
Dhananjaya V
DV
Resta
Nicoletta
N
Shong
Minho
M
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*
D050796:STAT3 Transcription Factor; D051096:Proto-Oncogene Proteins c-ret; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases