Posttranslational regulation of liver kinase B1 in human cancer

Abstract

Liver kinase B1 (LKB1) is a serine-threonine kinase that participates in multiple cellular and biological processes, including energy metabolism, cell polarity, cell proliferation, cell migration, and many others. LKB1 is initially identified as a germline-mutated causative gene in Peutz-Jeghers syndrome and is commonly regarded as a tumor suppressor due to frequent inactivation in a variety of cancers. LKB1 directly binds and activates its downstream kinases including the AMP-activated protein kinase (AMPK) and AMPK-related kinases by phosphorylation, which has been intensively investigated for the past decades. An increasing number of studies have uncovered the posttranslational modifications (PTMs) of LKB1 and consequent changes in its localization, activity, and interaction with substrates. The alteration in LKB1 function as a consequence of genetic mutations and aberrant upstream signaling regulation leads to tumor development and progression. Here, we review current knowledge about the mechanism of LKB1 in cancer and the contributions of PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, prenylation, and others, to the regulation of LKB1 function, offering new insights into the therapeutic strategies in cancer. Liver kinase B1 (LKB1) is a serine-threonine kinase that participates in multiple cellular and biological processes, including energy metabolism, cell polarity, cell proliferation, cell migration, and many others. LKB1 is initially identified as a germline-mutated causative gene in Peutz-Jeghers syndrome and is commonly regarded as a tumor suppressor due to frequent inactivation in a variety of cancers. LKB1 directly binds and activates its downstream kinases including the AMP-activated protein kinase (AMPK) and AMPK-related kinases by phosphorylation, which has been intensively investigated for the past decades. An increasing number of studies have uncovered the posttranslational modifications (PTMs) of LKB1 and consequent changes in its localization, activity, and interaction with substrates. The alteration in LKB1 function as a consequence of genetic mutations and aberrant upstream signaling regulation leads to tumor development and progression. Here, we review current knowledge about the mechanism of LKB1 in cancer and the contributions of PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, prenylation, and others, to the regulation of LKB1 function, offering new insights into the therapeutic strategies in cancer. Liver kinase B1 (LKB1), also known as serine-threonine kinase 11 (STK11), is the gene encoding an evolutionarily conserved serine/threonine kinase belonging to the calcium/calmodulin regulated kinase-like family (1Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. et al.A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.Nature. 1998; 391: 184-187Crossref PubMed Scopus (1353) Google Scholar, 2Ylikorkala A. Avizienyte E. Tomlinson I.P. Tiainen M. Roth S. Loukola A. et al.Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer.Hum. Mol. Genet. 1999; 8: 45-51Crossref PubMed Scopus (126) Google Scholar). LKB1 was initially identified as a causative gene with loss of function mutations responsible for the Peutz-Jeghers syndrome, a rare hereditary disease and the first cancer-susceptibility syndrome characterized by the predisposition of benign and malignant tumors of many organ systems (1Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. et al.A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.Nature. 1998; 391: 184-187Crossref PubMed Scopus (1353) Google Scholar). The somatic mutations of LKB1 in cancers are rare (3Avizienyte E. Roth S. Loukola A. Hemminki A. Lothe R.A. Stenwig A.E. et al.Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.Cancer Res. 1998; 58: 2087-2090PubMed Google Scholar, 4Guldberg P. thor Straten P. Ahrenkiel V. Seremet T. Kirkin A.F. Zeuthen J. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.Oncogene. 1999; 18: 1777-1780Crossref PubMed Google Scholar), except for non-small cell lung carcinoma (NSCLC) (5Matsumoto S. Iwakawa R. Takahashi K. Kohno T. Nakanishi Y. Matsuno Y. et al.Prevalence and specificity of LKB1 genetic alterations in lung cancers.Oncogene. 2007; 26: 5911-5918Crossref PubMed Scopus (229) Google Scholar, 6Koivunen J.P. Kim J. Lee J. Rogers A.M. Park J.O. Zhao X. et al.Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients.Br. J. Cancer. 2008; 99: 245-252Crossref PubMed Scopus (136) Google Scholar, 7Imielinski M. Berger A.H. Hammerman P.S. Hernandez B. Pugh T.J. Hodis E. et al.Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.Cell. 2012; 150: 1107-1120Abstract Full Text Full Text PDF PubMed Scopus (1382) Google Scholar, 8Shire N.J. Klein A.B. Golozar A. Collins J.M. Fraeman K.H. Nordstrom B.L. et al.STK11 (LKB1) mutations in metastatic NSCLC: prognostic value in the real world.PLoS One. 2020; 15e0238358Crossref PubMed Scopus (26) Google Scholar) and cervical carcinoma (9Wingo S.N. Gallardo T.D. Akbay E.A. Liang M.C. Contreras C.M. Boren T. et al.Somatic LKB1 mutations promote cervical cancer progression.PLoS One. 2009; 4: e5137Crossref PubMed Scopus (220) Google Scholar) with approximately 5% to 30% and 20% cases of LKB1 mutants, respectively. Studies have also reported the infrequently aberrant expression levels of LKB1 caused by somatic mutation or epigenetic alteration in several malignancies, including melanoma (4Guldberg P. thor Straten P. Ahrenkiel V. Seremet T. Kirkin A.F. Zeuthen J. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.Oncogene. 1999; 18: 1777-1780Crossref PubMed Google Scholar), colorectal cancer (10Dong S.M. Kim K.M. Kim S.Y. Shin M.S. Na E.Y. Lee S.H. et al.Frequent somatic mutations in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer.Cancer Res. 1998; 58: 3787-3790PubMed Google Scholar), breast cancer (11Esteller M. Avizienyte E. Corn P.G. Lothe R.A. Baylin S.B. Aaltonen L.A. et al.Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome.Oncogene. 2000; 19: 164-168Crossref PubMed Google Scholar), pancreatic neoplasm (12Sahin F. Maitra A. Argani P. Sato N. Maehara N. Montgomery E. et al.Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms.Mod. Pathol. 2003; 16: 686-691Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), and so on. In vivo studies using conditionally Lkb1-deleted mouse models and cancer cell lines have implicated the tumor suppressive role of LKB1 in different types of cancers, such as hepatocellular carcinoma (HCC) (13Nakau M. Miyoshi H. Seldin M.F. Imamura M. Oshima M. Taketo M.M. Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.Cancer Res. 2002; 62: 4549-4553PubMed Google Scholar), breast cancer (14McCarthy A. Lord C.J. Savage K. Grigoriadis A. Smith D.P. Weigelt B. et al.Conditional deletion of the Lkb1 gene in the mouse mammary gland induces tumour formation.J. Pathol. 2009; 219: 306-316Crossref PubMed Scopus (27) Google Scholar), and endometrial cancer (15Contreras C.M. Gurumurthy S. Haynie J.M. Shirley L.J. Akbay E.A. Wingo S.N. et al.Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas.Cancer Res. 2008; 68: 759-766Crossref PubMed Scopus (89) Google Scholar). Additionally, loss of LKB1 is associated with poor prognosis in patients with cancer. Remarkably, concomitant LKB1 deficiency with Kirsten rat sarcoma viral oncogene homolog (KRAS) or phosphatase and tensin homolog (PTEN) mutation accelerates cancer progression and induces immunosuppressive tumor microenvironment (16Ji H. Ramsey M.R. Hayes D.N. Fan K. P. et lung cancer and 2007; PubMed Scopus Google Scholar, J.P. D. R.A. et with to promote pancreatic cancer of Full Text Full Text PDF PubMed Scopus Google Scholar, I. P. A. S. F. N. et of LKB1 metastatic 2020; PubMed Scopus Google Scholar, P.S. S. T. et al.Loss of LKB1 and tumor suppressor in the induces PubMed Scopus Google Scholar, M. T. P. and in lung PubMed Scopus Google Scholar). studies have also uncovered its function in several cancers X. Liang H. X. B. of kinase B1 poor prognosis in hepatocellular J. Google Scholar, R. A. F. et al.A LKB1 and PubMed Scopus Google Scholar, Y. B. J.P. et and are in Full Text Full Text PDF PubMed Scopus Google Scholar, F. et and of LKB1 is for cancer cell energy Full Text Full Text PDF PubMed Scopus (89) Google Scholar, I. D. X. et of LKB1 and by energy in PubMed Scopus Google Scholar). LKB1 a with the and the mouse protein also known as protein which the of LKB1 and its J. A.F. M. A. M. et with to and LKB1 in the J. 2003; PubMed Scopus Google Scholar). LKB1 as a kinase that a of cellular the of AMP-activated protein kinase (AMPK) and AMPK-related including kinases to as N.J. D. the regulation of kinases and by 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), kinases Y. Miyoshi H. Oshima M. M. Taketo M.M. of by the kinase 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. B. of kinase and of by the tumor suppressor protein 2007; PubMed Scopus Google Scholar), kinase family A. 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C.M. A. a protein to the Peutz-Jeghers syndrome kinase Mol. Genet. PubMed Google Scholar), gene F. LKB1 with and is for Full Text Full Text PDF PubMed Scopus Google Scholar), tumor suppressor kinase and M. J. A. S. J. et al.A genetic an the 16: PubMed Scopus Google Scholar), tumor and progression. the downstream a of studies has been to the of posttranslational modifications (PTMs) of LKB1 its have that PTMs, including phosphorylation, ubiquitination, SUMOylation, prenylation, and others, or the localization, and function of In we review of the cancer in of and the therapeutic in cancer. The gene is the of and protein of the LKB1 including the LKB1 a M.C. S. et al.A of the tumour suppressor LKB1 is for J. 2008; PubMed Scopus Google Scholar), and the the and kinase R. A. F. et al.A LKB1 and PubMed Scopus Google Scholar) In et identified of LKB1 by in and and the are into and M.C. 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M. A. M. et with to and LKB1 in the J. 2003; PubMed Scopus Google Scholar). The of the by E. et that a its to and binds to the kinase of LKB1 its which the interaction and LKB1 and the of LKB1 from the to the The interaction with also the and the of the of LKB1 in a for its E. M. of the an mechanism of kinase 2009; PubMed Scopus Google Scholar, J. A. J. M. et signaling and to in Full Text Full Text PDF PubMed Scopus Google Scholar). In cancer LKB1 is also in with and the of which induces the of and the expression of in X. Zhao et an a to PubMed Scopus Google Scholar). In of the mechanism of LKB1 in and mouse the is reported to with LKB1 its and LKB1 in the Y. M. et LKB1 and activates 2012; 8: PubMed Scopus Google Scholar). in the LKB1 binds to and the downstream is that the by has that the of the of and the of LKB1 to to and from to in B. M. M. Y. et is a for and as a and Full Text Full Text PDF PubMed Google Scholar). the of LKB1 is for its and interaction with downstream substrates. 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A.B. et inactivation to metastatic PubMed Scopus Google Scholar). its role in LKB1 the of in the and a of by the of and In the of is to and downstream of such as protein and which promote tumor and M. J. A. S. J. et al.A genetic an the 16: PubMed Scopus Google Scholar). studies have also the role of LKB1 in and cell LKB1 cancer by an protein the which R. N. LKB1 by Res. PubMed Scopus Google Scholar). In the cancer LKB1 and to and and to the of and In the of impaired and to R. R. E. J. J. et al.A mouse LKB1 as an Genet. PubMed Scopus (27) Google Scholar). In the protein regulated and in the to promote the tumor and the the of such as the of E. L.J. et in non-small cell lung PubMed Scopus Google Scholar). a conditionally and and that LKB1 inactivation the of lung tumor and leads to the of cell into which by LKB1 M. H. et and to an in lung PubMed Scopus Google Scholar), of the role of LKB1 in cell of LKB1 induces expression of such as and and the of in breast cancer S. A. N. P. A. et of tumor suppressor LKB1 by cancer in breast cancer of PubMed Scopus Google Scholar). studies in of cancers with LKB1 mutation and in with gene mutations the role of LKB1 in that LKB1 inactivation lung adenocarcinoma with loss to cell carcinoma H. S. T. S. et inactivation lung cancer by Scholar). is of of homolog and suppressor of and the of M. et cell 2008; PubMed Scopus Google Scholar). of activates the of including and H. S. T. S. et inactivation lung cancer by Scholar). and from LKB1 deficiency also the X. F. Y. F. R. et of lung adenocarcinoma in with Lkb1 deficiency to cell PubMed Scopus Google Scholar, Y. X. F. X. R. et of lung adenocarcinoma PubMed Scopus (89) Google Scholar). of the in lung adenocarcinoma provokes and induces the of lung adenocarcinoma into lung cell carcinoma X. F. Y. F. R. et of lung adenocarcinoma in with Lkb1 deficiency to cell PubMed Scopus Google Scholar). that into the and by to the to the of lung adenocarcinoma to lung cell carcinoma Y. X. F. X. 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