Mahanine reverses an epigenetically silenced tumor suppressor gene RASSF1A in human prostate cancer cells.
It is becoming clear that frequent epigenetic silencing of tumor suppressor genes could be responsible for the development of cancer in various organs. Several recent reports suggest that suppression of RASSF1A is associated with the advanced grade and stage of prostate cancer and many other cancers. In this investigation, we demonstrated that, mahanine, a plant derived carbazole alkaloid, induced RASSF1A expression in both androgen-responsive (LNCaP) and androgen-negative (PC3) prostate cancer cells by inhibiting DNA methyltransferase (DNMT) activity. Mahanine-induced expression of RASSF1A in turn significantly reduced cyclin D1 but not other cyclins. To understand the inverse relationship between RASSF1A and cyclin D1, we observed that mahanine treatment down-regulates cyclin D1 and addition of RASSF1A siRNA prevented this inhibition. This study show for the first time that mahanine can reverse an epigenetically silenced gene, RASSF1A in prostate cancer cells by inhibiting DNMT activity that in turn down-regulates a key cell cycle regulator, cyclin D1. Mahanine therefore, promises an encouraging therapeutic choice for advanced prostatic cancer.
Jagadeesh
Shankar
S
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057, USA.
Sinha
Swati
S
Department of Zoology, Visva-Bharati University, Santineketan, India.
Pal
Bikas C
BC
Indian Institute of Chemical Biology, Kolkata, India.
Bhattacharya
Samir
S
Department of Zoology, Visva-Bharati University, Santineketan, India.
Banerjee
Partha P
PP
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057, USA. Electronic address: ppb@georgetown.edu.
D000470:Alkaloids / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
D000470:Alkaloids; D002227:Carbazoles; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C465290:mahanine; D019938:Cyclin D1; D004248:DNA (Cytosine-5-)-Methyltransferases