SOX2 function and Hedgehog signaling pathway are co-conspirators in promoting androgen independent prostate cancer.
Developmentally inclined hedgehog (HH) signaling pathway and pluripotency inducing transcription factor SOX2 have been known to work syngerstically during cellular reprogramming events to facilitate efficient differentiation. Hence, it is not surprising that both the factors are actively involved in arbitrating malignant growth, including prostate cancer progression. Here, we have described in details the potential mechanisms by which SOX2 effects neoplastic characteristics in prostate cancer and investigated the consequences of simultaneous down-regulation of SOX2 and HH pathway in androgen-independent human prostate cancer cells. Expression of SOX2 has been determined by qRT-PCR, western blot, immunohistochemistry and immunocytochemistry analyses; its functional role determined by gene knockdown using RNAi and over-expression via chemical activation in HaCaT, DU145 and PC-3 cells. Changes in level of cell proliferation, migration and apoptosis profiles were measured by MTT, FACS, chromatin condensation and scratch assays respectively. SOX2 was expressed in all the three cell lines and its inhibition reduced cell proliferation and induced apoptosis. Most importantly, when both SOX2 and HH pathway were targeted simultaneously, cell proliferation was greatly reduced, apoptotic cell population increased drastically and migration potential was reduced. Moreover, gene expression of EMT markers such as E-cadherin and apoptosis related Bcl-2 and Bax was also investigated wherein decrease in E-cadherin and Bcl-2 levels and increase in Bax expression further substantiating our claim. These findings could provide the basis for a novel therapeutic strategy targeting both the effector i.e. SOX2 and perpetuator i.e. HH pathway of aggressive tumorigenic properties in androgen independent prostate cancer.
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Swayamsiddha
S
Kar
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Dipta
D
Sengupta
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Moonmoon
M
Deb
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Nibedita
N
Pradhan
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India. Electronic address: samirp@nitrkl.ac.in.
Samir Kumar
SK
Patra
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
D053823:Hedgehog Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
Cell signaling; Gene silencing; HH signaling; Prostate cancer; SOX2; Transcription factor