Increased Expression of Histone Demethylase JHDM1D Under Nutrient Starvation Suppresses Tumor Growth Via Down-regulating Angiogenesis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Dec 7

PMID 22143793

Citations 37

Authors

Tsuyoshi Osawa

Masashi Muramatsu

Feng Wang

Rika Tsuchida

Tatsuhiko Kodama

Takashi Minami

Masabumi Shibuya

Affiliations

Soon will be listed here.

Abstract

Histone demethylase JHDM1D (also known as KDM7A) modifies the level of methylation in histone and participates in epigenetic gene regulation; however, the role of JHDM1D in tumor progression is unknown. Here, we show that JHDM1D plays a tumor-suppressive role by regulating angiogenesis. Expression of JHDM1D was increased in mouse and human cancer cells under long-term nutrient starvation in vitro. Expression of JHDM1D mRNA was increased within avascular tumor tissue at the preangiogenic switch, along with increased expression of angiogenesis-regulating genes such as Vegf-A. Stable expression of JHDM1D cDNA or siRNA silencing of JHDM1D in cancer cells did not affect cell proliferation, anchorage-independent cell growth, or cell cycle progression in vitro. Notably, JHDM1D-expressing mouse melanoma (B16) and human cervical carcinoma (HeLa) cells exhibited significantly slower tumor growth in vivo compared with the original cells. This reduction in tumor growth was associated with decreased formation of CD31(+) blood vessels and reduced infiltration of CD11b(+) macrophage linage cells into tumor tissues. Expression of multiple angiogenic factors such as VEGF-B and angiopoietins was decreased in tumor xenografts of JHDM1D-expressing B16 and HeLa cells. Our results provide evidence that increased JHDM1D expression suppressed tumor growth by down-regulating angiogenesis under nutrient starvation.

Citing Articles

Current advances and future directions in targeting histone demethylases for cancer therapy.

Shin J, Yoo H, Roe J Mol Cells. 2025; 48(3):100192.

PMID: 39938867 PMC: 11889978. DOI: 10.1016/j.mocell.2025.100192.

The Histone Lysine Demethylase KDM7A Contributes to Reward Memory via Fscn1-Induced Synaptic Plasticity in the Medial Prefrontal Cortex.

Yang Z, Yu D, Gao F, Zhou D, Wu Y, Yang X Adv Sci (Weinh). 2025; 12(10):e2405352.

PMID: 39836528 PMC: 11905110. DOI: 10.1002/advs.202405352.

PARP1 acetylation at K119 is essential in regulating the progression and proliferation of cervical cancer cells.

Yang L, Zhang X, Cao Y, Shi L, Xie S, Yang Y Med Oncol. 2024; 41(11):273.

PMID: 39400626 DOI: 10.1007/s12032-024-02315-7.

Combined expression of JHDM1D/KDM7A gene and long non-coding RNA RP11-363E7.4 as a biomarker for urothelial cancer prognosis.

Silva G, Pereira I, Lima A, Almeida T, Savio A, Costa R Genet Mol Biol. 2024; 47(3):e20230265.

PMID: 39136575 PMC: 11320665. DOI: 10.1590/1678-4685-GMB-2023-0265.

Starvation induces hepatopancreas atrophy in Chinese mitten crab (Eriocheir sinensis) by inhibiting angiogenesis.

Liu H, Feng Y, Yang M, Huang Y, Li M, Geng Y BMC Genomics. 2023; 24(1):612.

PMID: 37828424 PMC: 10571328. DOI: 10.1186/s12864-023-09620-x.

References

Osawa T, Tsuchida R, Muramatsu M, Yuasa Y, Shibuya M . Human glioblastoma cells exposed to long-term hypoxia and nutrient starvation stimulated induction of secondary T-cell leukemia in mice. Blood Cancer J. 2012; 1(2):e6. PMC: 3255269. DOI: 10.1038/bcj.2011.5. View

Tsukada Y, Ishitani T, Nakayama K . KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development. Genes Dev. 2010; 24(5):432-7. PMC: 2827838. DOI: 10.1101/gad.1864410. View

Horton J, Upadhyay A, Qi H, Zhang X, Shi Y, Cheng X . Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat Struct Mol Biol. 2009; 17(1):38-43. PMC: 2849977. DOI: 10.1038/nsmb.1753. View

Das B, Yeger H, Tsuchida R, Torkin R, Gee M, Thorner P . A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res. 2005; 65(16):7267-75. DOI: 10.1158/0008-5472.CAN-04-4575. View

Klose R, Kallin E, Zhang Y . JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006; 7(9):715-27. DOI: 10.1038/nrg1945. View

Hsia D, Tepper C, Pochampalli M, Hsia E, Izumiya C, Huerta S . KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc Natl Acad Sci U S A. 2010; 107(21):9671-6. PMC: 2906833. DOI: 10.1073/pnas.1000401107. View

Ikeda E, Achen M, Breier G, Risau W . Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem. 1995; 270(34):19761-6. DOI: 10.1074/jbc.270.34.19761. View

Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T . Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010; 468(7325):824-8. DOI: 10.1038/nature09557. View

Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz C . Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet. 2005; 42(10):780-6. PMC: 1735927. DOI: 10.1136/jmg.2004.029439. View

10.

Huang C, Xiang Y, Wang Y, Li X, Xu L, Zhu Z . Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Res. 2010; 20(2):154-65. DOI: 10.1038/cr.2010.5. View

11.

Liu W, Tanasa B, Tyurina O, Zhou T, Gassmann R, Liu W . PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature. 2010; 466(7305):508-12. PMC: 3059551. DOI: 10.1038/nature09272. View

12.

Qi H, Sarkissian M, Hu G, Wang Z, Bhattacharjee A, Gordon D . Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature. 2010; 466(7305):503-7. PMC: 3072215. DOI: 10.1038/nature09261. View

13.

Shibuya M, Kaziro Y . Studies on stringent control in a cell-free system. Regulation by guanosine-5'-diphosphate-3'-diphosphate of the synthesis of elongation factor Tu. J Biochem. 1979; 86(2):403-11. DOI: 10.1093/oxfordjournals.jbchem.a132539. View

14.

Escudier B, Eisen T, Stadler W, Szczylik C, Oudard S, Siebels M . Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356(2):125-34. DOI: 10.1056/NEJMoa060655. View

15.

Chadwick B, Theil T, Heath S, Wilkinson D, Frischauf A . PHF2, a novel PHD finger gene located on human chromosome 9q22. Mamm Genome. 1999; 10(3):294-8. DOI: 10.1007/s003359900989. View

16.

Ferrara N, Kerbel R . Angiogenesis as a therapeutic target. Nature. 2005; 438(7070):967-74. DOI: 10.1038/nature04483. View

17.

Sandler A, Gray R, Perry M, Brahmer J, Schiller J, Dowlati A . Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355(24):2542-50. DOI: 10.1056/NEJMoa061884. View

18.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-42. DOI: 10.1056/NEJMoa032691. View

19.

Osawa T, Muramatsu M, Watanabe M, Shibuya M . Hypoxia and low-nutrition double stress induces aggressiveness in a murine model of melanoma. Cancer Sci. 2009; 100(5):844-51. PMC: 11159247. DOI: 10.1111/j.1349-7006.2009.01105.x. View

20.

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View