The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas.
Malignant meningiomas are a rare meningioma subtype and tend to have post-surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N-terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1-PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas.
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Mao-Hua
MH
Ding
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Zhen
Z
Wang
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Lei
L
Jiang
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Hua-Lin
HL
Fu
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Jie
J
Gao
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Xian-Bin
XB
Lin
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Chun-Lei
CL
Zhang
Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing 100700, China.
Zhen-Yang
ZY
Liu
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Yi-Fei
YF
Shi
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Guan-Zhong
GZ
Qiu
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Yue
Y
Ma
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Da-Xiang
DX
Cui
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: huguohan6504@sina.com.
Guo-Han
GH
Hu
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: weilinjin@yahoo.com.
Wei-Lin
WL
Jin
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry*; D044127:Epigenesis, Genetic; D005260:Female; D015696:Gene Products, tat / Q000737:chemistry*; D016147:Genes, Tumor Suppressor; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006657:Histones / Q000737:chemistry; D006801:Humans; D008297:Male; D008579:Meningioma / Q000378:metabolism / Q000628:therapy*; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000737:chemistry*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015696:Gene Products, tat; D006657:Histones; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C486715:TXNIP protein, human; D014157:Transcription Factors; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human
Histone methyltransferase; Meningioma; PR domain; RIZ1; TAT protein transduction; Tumor suppressor