Chromatin protein PC4 is downregulated in breast cancer to promote disease progression: Implications of miR-29a
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Sweta Sikder1, Sujata Kumari1, Manoj Kumar1, Shrinka Sen1, Namrata Bora Singhal2, Srikumar Chellappan2, Mukul Godbole3, Pratik Chandrani3, Amit Dutt3, Kodaganur S. Gopinath4 and Tapas K. Kundu1
1 Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
2 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
3 Integrated Cancer Genomics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Mumbai, India
4 Bangalore Institute of Oncology, Bangalore, India
|Tapas K. Kundu,
Keywords: tumour suppressor; non-histone chromatin protein; oncomiR; matrix metalloproteinases; p53 activation
Received: May 15, 2019 Accepted: October 19, 2019 Published: December 03, 2019
The human transcriptional coactivator PC4 has numerous roles to play in the cell. Other than its transcriptional coactivation function, it facilitates chromatin organization, DNA damage repair, viral DNA replication, etc. Although it was found to be an essential protein in vivo, the importance of this multifunctional protein in the regulation of different cellular pathways has not been investigated in details, particularly in oncogenesis. In this study, PC4 downregulation was observed in a significant proportion of mammary tissues obtained from Breast cancer patient samples as well as in a subset of highly invasive and metastatic Breast cancer patient-derived cell lines. We have identified a miRNA, miR-29a which potentially reduce the expression of PC4 both in RNA and protein level. This miR-29a was found to be indeed overexpressed in a substantial number of Breast cancer patient samples and cell lines as well, suggesting one of the key mechanisms of PC4 downregulation. Stable Knockdown of PC4 in MCF7 cells induced its migratory as well as invasive properties. Furthermore, in an orthotopic breast cancer mice model system; we have shown that reduced expression of PC4 enhances the tumorigenic potential substantially. Absence of PC4 led to the upregulation of several genes involved in Epithelial to Mesenchymal Transition (EMT), indicating the possible mechanism of uniform tumour progression in the orthotropic mice. Collectively these data establish the role of PC4 in tumour suppression.
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