Targeted Knockdown of the Kinetochore Protein D40/Knl-1 Inhibits Human Cancer in a P53 Status-Independent Manner

Overview

Journal Sci Rep

Specialty Science

Date 2015 Sep 9

PMID 26348410

Citations 9

Authors

Yuri N Urata

Fumitaka Takeshita

Hiroki Tanaka

Takahiro Ochiya

Masato Takimoto

Affiliations

Soon will be listed here.

Abstract

The D40 gene encodes a kinetochore protein that plays an essential role in kinetochore formation during mitosis. Short inhibitory RNA against D40, D40 siRNA, has been shown to deplete the D40 protein in the human cancer cell line HeLa, which harbors wild-type p53, and this activity was followed by the significant inhibition of cell growth and induction of apoptotic cell death. The p53-null cancer cell line, PC-3M-luc, is also sensitive to the significant growth inhibition and cell death induced by D40 siRNA. The growth of PC-3M-luc tumors transplanted into nude mice was inhibited by the systemic administration of D40 siRNA and the atelocollagen complex. Furthermore, D40 siRNA significantly inhibited growth and induced apoptotic cell death in a cell line with a gain-of-function (GOF) mutation in p53, MDA-MB231-luc, and also inhibited the growth of tumors transplanted into mice when administered as a D40 siRNA/atelocollagen complex. These results indicated that D40 siRNA induced apoptotic cell death in human cancer cell lines, and inhibited their growth in vitro and in vivo regardless of p53 status. Therefore, D40 siRNA is a potential candidate anti-cancer reagent.

Citing Articles

Role of Kinetochore Scaffold 1 (KNL1) in Tumorigenesis and Tumor Immune Microenvironment in Pan-Cancer: Bioinformatics Analyses and Validation of Expression.

Ding Y, Wang K, Zhao S, Li Y, Qiu W, Zhu C Int J Gen Med. 2023; 16:4883-4906.

PMID: 37928953 PMC: 10625436. DOI: 10.2147/IJGM.S424245.

KNL1 is a prognostic and diagnostic biomarker related to immune infiltration in patients with uterine corpus endometrial carcinoma.

He K, Li J, Huang X, Zhao W, Wang K, Wang T Front Oncol. 2023; 13:1090779.

PMID: 36776306 PMC: 9913269. DOI: 10.3389/fonc.2023.1090779.

High expression of KNL1 in prostate adenocarcinoma is associated with poor prognosis and immune infiltration.

Zhang Y, Ji Q, Wang J, Dong Y, Pang M, Fu S Front Genet. 2023; 13:1100787.

PMID: 36685823 PMC: 9853456. DOI: 10.3389/fgene.2022.1100787.

Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors.

Iegiani G, Di Cunto F, Pallavicini G Cell Death Dis. 2021; 12(11):956.

PMID: 34663805 PMC: 8523548. DOI: 10.1038/s41419-021-04259-6.

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis.

Zhou X, Zhi Y, Yu J, Xu D Int J Mol Sci. 2020; 21(5).

PMID: 32121580 PMC: 7084222. DOI: 10.3390/ijms21051691.

References

Kamada S, Kusano H, Fujita H, Ohtsu M, Koya R, Kuzumaki N . A cloning method for caspase substrates that uses the yeast two-hybrid system: cloning of the antiapoptotic gene gelsolin. Proc Natl Acad Sci U S A. 1998; 95(15):8532-7. PMC: 21110. DOI: 10.1073/pnas.95.15.8532. View

Takimoto M, Wei G, Dosaka-Akita H, Mao P, Kondo S, Sakuragi N . Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers. Br J Cancer. 2002; 86(11):1757-62. PMC: 2375411. DOI: 10.1038/sj.bjc.6600328. View

Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M . A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1. Nat Cell Biol. 2004; 6(11):1135-41. DOI: 10.1038/ncb1187. View

Sasao T, Itoh N, Takano H, Watanabe S, Wei G, Tsukamoto T . The protein encoded by cancer/testis gene D40/AF15q14 is localized in spermatocytes, acrosomes of spermatids and ejaculated spermatozoa. Reproduction. 2004; 128(6):709-16. DOI: 10.1530/rep.1.00312. View

Simpson A, Caballero O, Jungbluth A, Chen Y, Old L . Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005; 5(8):615-25. DOI: 10.1038/nrc1669. View

Takeshita F, Minakuchi Y, Nagahara S, Honma K, Sasaki H, Hirai K . Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc Natl Acad Sci U S A. 2005; 102(34):12177-82. PMC: 1183487. DOI: 10.1073/pnas.0501753102. View

Cheeseman I, Chappie J, Wilson-Kubalek E, Desai A . The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell. 2006; 127(5):983-97. DOI: 10.1016/j.cell.2006.09.039. View

Hanai K, Takeshita F, Honma K, Nagahara S, Maeda M, Minakuchi Y . Atelocollagen-mediated systemic DDS for nucleic acid medicines. Ann N Y Acad Sci. 2006; 1082:9-17. DOI: 10.1196/annals.1348.010. View

Muller P, Vousden K . Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014; 25(3):304-17. PMC: 3970583. DOI: 10.1016/j.ccr.2014.01.021. View

10.

Wei G, Takimoto M, Yoshida I, Mao P, Koya R, Miura T . Chromosomal assignment of a novel human gene D40. Nucleic Acids Symp Ser. 2000; (42):71-2. DOI: 10.1093/nass/42.1.71. View

11.

Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C . AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Oncogene. 2000; 19(38):4446-50. DOI: 10.1038/sj.onc.1203789. View

12.

Yu S, Wang H, Poitras M, Coombs C, Bowers W, Federoff H . Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002; 297(5579):259-63. DOI: 10.1126/science.1072221. View

13.

Jenkins D, Yu S, Hornig Y, Purchio T, Contag P . In vivo monitoring of tumor relapse and metastasis using bioluminescent PC-3M-luc-C6 cells in murine models of human prostate cancer. Clin Exp Metastasis. 2004; 20(8):745-56. DOI: 10.1023/b:clin.0000006817.25962.87. View

14.

Cheeseman I, Niessen S, Anderson S, Hyndman F, Yates 3rd J, Oegema K . A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev. 2004; 18(18):2255-68. PMC: 517519. DOI: 10.1101/gad.1234104. View

15.

Lane D . Cancer. p53, guardian of the genome. Nature. 1992; 358(6381):15-6. DOI: 10.1038/358015a0. View

16.

Blagosklonny M, Prabhu N, El-Deiry W . Defects in p21WAF1/CIP1, Rb, and c-myc signaling in phorbol ester-resistant cancer cells. Cancer Res. 1997; 57(2):320-5. View

17.

Yamauchi S, Hou Y, Guo A, Hirata H, Nakajima W, Yip A . p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J Cell Biol. 2014; 204(7):1191-207. PMC: 3971739. DOI: 10.1083/jcb.201309107. View

18.

Jamieson C, Govaerts C, Abramowicz M . Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet. 1999; 65(5):1465-9. PMC: 1288302. DOI: 10.1086/302640. View

19.

Rho J, Choi Y, Ryoo B, Na I, Yang S, Kim C . p53 enhances gefitinib-induced growth inhibition and apoptosis by regulation of Fas in non-small cell lung cancer. Cancer Res. 2007; 67(3):1163-9. DOI: 10.1158/0008-5472.CAN-06-2037. View

20.

Niikura Y, Dixit A, Scott R, Perkins G, Kitagawa K . BUB1 mediation of caspase-independent mitotic death determines cell fate. J Cell Biol. 2007; 178(2):283-96. PMC: 2064447. DOI: 10.1083/jcb.200702134. View