<em>STK31</em> upregulation is associated with chromatin remodeling in gastric cancer and induction of tumorigenicity in a xenograft mouse model

Bae,Dong Hyuck; Kim,Hee-Jin; Yoon,Byoung-Ha; Park,Jong-Lyul; Kim,Mirang; Kim,Seon-Kyu; Kim,Seon-Young; Lee,Sang-Il; Song,Kyu-Sang; Kim,Yong Sung

doi:10.3892/or.2021.7993

STK31 upregulation is associated with chromatin remodeling in gastric cancer and induction of tumorigenicity in a xenograft mouse model

Authors:
- Dong Hyuck Bae
- Hee-Jin Kim
- Byoung-Ha Yoon
- Jong-Lyul Park
- Mirang Kim
- Seon-Kyu Kim
- Seon-Young Kim
- Sang-Il Lee
- Kyu-Sang Song
- Yong Sung Kim
View Affiliations

Affiliations: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea, Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea, Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Republic of Korea, Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea, Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
Published online on: February 23, 2021 https://doi.org/10.3892/or.2021.7993
Article Number: 42
Copyright: © Bae et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. Our previous study showed that global methylation of promoters may increase or decrease during the transition from gastric mucosa to intestinal metaplasia (IM) to gastric cancer (GC). Here, CpG hypomethylation of the serine/threonine kinase STK31 promoter in IM and GC was detected in a reduced representation bisulfite sequencing database. STK31 hypomethylation, which resulted in its upregulation in 120 cases of primary GC, was confirmed. Using public genome‑wide histone modification data, upregulation of STK31 promoter activity was detected in primary GC but not in normal mucosae, suggesting that STK31 may be repressed in gastric mucosa but activated in GC as a consequence of hypomethylation‑associated chromatin remodeling. STK31 knockdown suppressed the proliferation, colony formation and migration activities of GC cells in vitro, whereas stable overexpression of STK31 promoted the proliferation, colony formation, and migration activities of GC cells in vitro and tumorigenesis in nude mice. Patients with GC in which STK31 was upregulated exhibited significantly shorter survival times in a combined cohort. Thus, activation of STK31 by chromatin remodeling may be associated with gastric carcinogenesis and also may help predict GC prognosis.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, Andreozzi F, Ventriglia J, Savastano B, Mabilia A, et al: Treatment of gastric cancer. World J Gastroenterol. 20:1635–1649. 2014. View Article : Google Scholar : PubMed/NCBI
3	Matsuoka T and Yashiro M: Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol. 24:2818–2832. 2018. View Article : Google Scholar : PubMed/NCBI
4	Correa P: Human gastric carcinogenesis: A multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 52:6735–6740. 1992.PubMed/NCBI
5	Jones PA and Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 3:415–428. 2002. View Article : Google Scholar : PubMed/NCBI
6	Szyf M, Pakneshan P and Rabbani SA: DNA methylation and breast cancer. Biochem Pharmacol. 68:1187–1197. 2004. View Article : Google Scholar : PubMed/NCBI
7	Upchurch GM, Haney SL and Opavsky R: Aberrant promoter hypomethylation in CLL: Does it matter for disease development? Front Oncol. 6:1822016. View Article : Google Scholar : PubMed/NCBI
8	Kim HJ, Kang TW, Haam K, Kim M, Kim SK, Kim SY, Lee SI, Song KS, Jeong HY and Kim YS: Whole genome MBD-seq and RRBS analyses reveal that hypermethylation of gastrointestinal hormone receptors is associated with gastric carcinogenesis. Exp Mol Med. 50:1–14. 2018. View Article : Google Scholar
9	Bao J, Wang L, Lei J, Hu Y, Liu Y, Shen H, Yan W and Xu C: STK31(TDRD8) is dynamically regulated throughout mouse spermatogenesis and interacts with MIWI protein. Histochem Cell Biol. 137:377–389. 2012. View Article : Google Scholar : PubMed/NCBI
10	Fok KL, Chen H, Ruan YC and Chan HC: Novel regulators of spermatogenesis. Semin Cell Dev Biol. 29:31–42. 2014. View Article : Google Scholar : PubMed/NCBI
11	Sabeur K, Ball BA, Corbin CJ and Conley A: Characterization of a novel, testis-specific equine serine/threonine kinase. Mol Reprod Dev. 75:867–873. 2008. View Article : Google Scholar : PubMed/NCBI
12	Xiao Y, Pollack D, Andrusier M, Levy A, Callaway M, Nieves E, Reddi P and Vigodner M: Identification of cell-specific targets of sumoylation during mouse spermatogenesis. Reproduction. 151:149–166. 2016. View Article : Google Scholar : PubMed/NCBI
13	Yokoe T, Tanaka F, Mimori K, Inoue H, Ohmachi T, Kusunoki M and Mori M: Efficient identification of a novel cancer/testis antigen for immunotherapy using three-step microarray analysis. Cancer Res. 68:1074–1082. 2008. View Article : Google Scholar : PubMed/NCBI
14	Kuo PL, Huang YL, Hsieh CC, Lee JC, Lin BW and Hung LY: STK31 is a cell-cycle regulated protein that contributes to the tumorigenicity of epithelial cancer cells. PLoS One. 9:e933032014. View Article : Google Scholar : PubMed/NCBI
15	Fok KL, Chung CM, Yi SQ, Jiang X, Sun X, Chen H, Chen YC, Kung HF, Tao Q, Diao R, et al: STK31 maintains the undifferentiated state of colon cancer cells. Carcinogenesis. 33:2044–2053. 2012. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Kim M, Kim JH, Jang HR, Kim HM, Lee CW, Noh SM, Song KS, Cho JS, Jeong HY, Hahn Y, et al: LRRC3B, encoding a leucine-rich repeat-containing protein, is a putative tumor suppressor gene in gastric cancer. Cancer Res. 68:7147–7155. 2008. View Article : Google Scholar : PubMed/NCBI
18	Huang KK, Ramnarayanan K, Zhu F, Srivastava S, Xu C, Tan AL, Lee M, Tay S, Das K, Xing M, et al: Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell. 33:137–150.e5. 2018. View Article : Google Scholar : PubMed/NCBI
19	Cancer Genome Atlas Research Network, . Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 513:202–209. 2014. View Article : Google Scholar : PubMed/NCBI
20	Lokk K, Modhukur V, Rajashekar B, Märtens K, Mägi R, Kolde R, Koltšina M, Nilsson TK, Vilo J, Salumets A and Tõnisson N: DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns. Genome Biol. 15:r542014. View Article : Google Scholar : PubMed/NCBI
21	Nazor KL, Altun G, Lynch C, Tran H, Harness JV, Slavin I, Garitaonandia I, Müller FJ, Wang YC, Boscolo FS, et al: Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell. 10:620–634. 2012. View Article : Google Scholar : PubMed/NCBI
22	Muratani M, Deng N, Ooi WF, Lin SJ, Xing M, Xu C, Qamra A, Tay ST, Malik S, Wu J, et al: Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements. Nat Commun. 5:43612014. View Article : Google Scholar : PubMed/NCBI
23	Lee J, Sohn I, Do IG, Kim KM, Park SH, Park JO, Park YS, Lim HY, Sohn TS, Bae JM, et al: Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery. PLoS One. 9:e901332014. View Article : Google Scholar : PubMed/NCBI
24	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
25	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
26	Berdasco M and Esteller M: Aberrant epigenetic landscape in cancer: How cellular identity goes awry. Dev Cell. 19:698–711. 2010. View Article : Google Scholar : PubMed/NCBI
27	Zhuang M, Calabrese MF, Liu J, Waddell MB, Nourse A, Hammel M, Miller DJ, Walden H, Duda DM, Seyedin SN, et al: Structures of SPOP-substrate complexes: Insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol Cell. 36:39–50. 2009. View Article : Google Scholar : PubMed/NCBI
28	Kim MS, Je EM, Oh JE, Yoo NJ and Lee SH: Mutational and expressional analyses of SPOP, a candidate tumor suppressor gene, in prostate, gastric and colorectal cancers. APMIS. 121:626–633. 2013. View Article : Google Scholar : PubMed/NCBI
29	Correa P and Piazuelo MB: The gastric precancerous cascade. J Dig Dis. 13:2–9. 2012. View Article : Google Scholar : PubMed/NCBI
30	Mesquita P, Raquel A, Nuno L, Reis CA, Silva LF, Serpa J, Van Seuningen I, Barros H and David L: Metaplasia-a transdifferentiation process that facilitates cancer development: The model of gastric intestinal metaplasia. Crit Rev Oncog. 12:3–26. 2006. View Article : Google Scholar : PubMed/NCBI
31	Shin CM, Kim N, Chang H, Kim JS, Lee DH and Jung HC: Follow-up study on CDX1 and CDX2 mRNA expression in noncancerous gastric mucosae after Helicobacter pylori eradication. Dig Dis Sci. 61:1051–1059. 2016. View Article : Google Scholar : PubMed/NCBI
32	Tucci A, Poli L, Tosetti C, Biasco G, Grigioni W, Varoli O, Mazzoni C, Paparo GF, Stanghellini V and Caletti G: Reversal of fundic atrophy after eradication of Helicobacter pylori. Am J Gastroenterol. 93:1425–1431. 1998. View Article : Google Scholar : PubMed/NCBI
33	Sung JJ, Lin SR, Ching JY, Zhou LY, To KF, Wang RT, Leung WK, Ng EK, Lau JY, Lee YT, et al: Atrophy and intestinal metaplasia one year after cure of H. pylori infection: A prospective, randomized study. Gastroenterology. 119:7–14. 2000. View Article : Google Scholar : PubMed/NCBI
34	Ohkusa T, Fujiki K, Takashimizu I, Kumagai J, Tanizawa T, Eishi Y, Yokoyama T and Watanabe M: Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann Intern Med. 134:380–386. 2001. View Article : Google Scholar : PubMed/NCBI
35	Kang JM, Kim N, Shin CM, Lee HS, Lee DH, Jung HC and Song IS: Predictive factors for improvement of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication: A three-year follow-up study in Korea. Helicobacter. 17:86–95. 2012. View Article : Google Scholar : PubMed/NCBI
36	Choi E, Hendley AM, Bailey JM, Leach SD and Goldenring JR: Expression of activated ras in gastric chief cells of mice leads to the full spectrum of metaplastic lineage transitions. Gastroenterology. 150:918–930.e13. 2016. View Article : Google Scholar : PubMed/NCBI
37	Kensler TW, Spira A, Garber JE, Szabo E, Lee JJ, Dong Z, Dannenberg AJ, Hait WN, Blackburn E, Davidson NE, et al: Transforming cancer prevention through precision medicine and immune-oncology. Cancer Prev Res (Phila). 9:2–10. 2016. View Article : Google Scholar : PubMed/NCBI