Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Oncogenesis
J-Y ChuangT-I Hsu

Abstract

Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1-CYP17A1-DHEA axis, whi...Continue Reading

References

Mar 30, 1999·Brain Research. Molecular Brain Research·S BastianettoR Quirion
May 9, 2002·Molecular and Cellular Endocrinology·Lu YuElise P Gomez-Sanchez
May 13, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jun Ming WangRoberta Diaz Brinton
Jan 12, 2007·Biochemical and Biophysical Research Communications·Vanessa DouetOlivier Le Saux
Apr 28, 2007·Proceedings of the National Academy of Sciences of the United States of America·Deepak KamnasaranAbhijit Guha
Oct 31, 2007·British Journal of Cancer·N M MhaidatP Hersey
Jun 10, 2009·Frontiers in Neuroendocrinology·Jean Luc Do RegoHubert Vaudry
Jul 22, 2009·Pharmacology & Therapeutics·Tangui Maurice, Tsung-Ping Su
Dec 16, 2010·BMC Genomics·Amandine EtcheverryJean Mosser
Apr 6, 2011·The Journal of Experimental Medicine·Sameer AgnihotriAbhijit Guha
Apr 14, 2011·The Journal of Physiology·João Paulo Gabriel CamporezCarla Roberta de Oliveira Carvalho
Dec 14, 2011·Oncogene·T-I HsuJ-J Hung
Feb 1, 2012·Drug Design, Development and Therapy·Yasser Rehman, Jonathan E Rosenberg
Jan 30, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jesus Garcia-DonasSusana Hernando
Mar 9, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Roberta FerraldeschiGerhardt Attard
Jul 3, 2013·EMBO Molecular Medicine·Florian A SiebzehnrublDennis A Steindler
Jul 31, 2013·International Journal of Molecular Sciences·Takashi KobayashiOsamu Ogawa
Nov 30, 2013·Pharmaceuticals·Yulian P RamirezAlonzo H Ross
Mar 22, 2014·Cancer Cell·Patricia A J Muller, Karen H Vousden
Nov 14, 2014·The FEBS Journal·Kate Beishline, Jane Azizkhan-Clifford
Nov 27, 2014·Nature Reviews. Neuroscience·Maria-Angeles ArevaloLuis M Garcia-Segura

❮ Previous
Next ❯

Citations

Mar 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gong-Jhe WuRuei-Ming Chen
Aug 5, 2020·Journal of Mammary Gland Biology and Neoplasia·Sharon Havusha-LauferItamar Barash
Dec 18, 2020·Cancer Cell International·Zhiyong WuHao Long
Mar 31, 2021·Molecular and Cellular Endocrinology·Sarah D Burris-Hiday, Emily E Scott
Jun 30, 2021·Free Radical Biology & Medicine·Hong-Yi LinTsung-I Hsu

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE4290

Methods Mentioned

BETA
surgical resection
immunoprecipitation assay
enzyme-linked immunosorbent assay
immunoprecipitation
PCR
electrophoresis

Software Mentioned

SurvExpress

Related Concepts

Related Feeds

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.