RESEARCH ARTICLE Tumorigenic PVT‐1 gene locus is governed by miR‐2909 RNomics Sameena Wani | Deepak Kaul Molecular Biology Unit, Experimental Medicine and Biotechnology Department, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Correspondence Deepak Kaul, Molecular Biology Unit, Experimental Medicine and Biotechnology Department, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Email: dkaul_24@hotmail.com Funding information Indian Council of Medical Research, ICMR, New Delhi, Government of India, Grant/ Award Number: 3/1/3/SRF‐2014/HRD Genomic regulation and functional significance of PVT‐1 gene locus, in the MYC‐driven cancers, has remained enigmatic ever since its discovery. With the present study, an attempt is made to establish that cellular AATF genome encoded miR‐2909 RNomics pathway involving crucial genes coding for KLF4, Deptor, mTORC1, STAT3, and p53 has the inherent capacity to ensure sustained co‐amplification of PVT‐1 gene locus together with c‐Myc gene. Based upon these results, we propose that miR‐2909 RNomics pathway may play a crucial role in the regulation of tumorigenic PVT‐1 gene locus. KEYWORDS c‐Myc, Deptor, KLF4, miR‐2909 RNomics, p53, PVT‐1gene locus 1 | INTRODUCTION There exists a general recognition of the fact that co‐amplification of genes coding for PVT‐1 and c‐Myc, within human genomic 8q24 region, has been frequently observed to occur in several solid tumours. 1,2 Ever since the discovery of PVT‐1 non‐protein coding gene locus that also yields a cluster of six microRNAs, this gene remained enigmatic because of its ability to provide site for tumori- genic and retroviral insertions. 2 The complexity of this gene locus does not end here since PVT‐1 is required for high c‐Myc protein levels in the cancer cells. 3 Paradoxically, the tumour suppressor protein p53 has been shown to regulate PVT‐1 gene and one of the six encoded microRNAs (miR‐1204) in a selective fashion. 4 This miR‐1204 has been found to increase cellular p53 levels. 4 A new dimension was added to the cancer biology by the findings that revealed as to how an interplay between cellular AATF genome encoded protein coding transcript and regulatory non‐coding microRNA designated miR‐ 2909 has the ability to govern many master‐genes (especially KLF4, c‐Myc, p53, p21, mTORC1) of crucial importance to the regulation of cellular processes, such as cell cycle progression, checkpoint control, and autophagy/apoptosis. 5-8 A surprising coupled with crucial func- tional link was found to exist between c‐Myc and mammalian target of rapamycin complex 1 (mTORC1)‐dependent increased expression of STAT3 as well as phosphorylation of the tumour‐suppressor eukaryotic translation initiation factor 4E (eIF4G) binding protein 1 (4EBP1) during Myc‐driven tumorigenesis. 9 Interestingly, AATF protein has been found to have the capacity to induce the expression of genes coding for p53, c‐Myc, Deptor, and REDD‐1. 5 The Deptor gene product is known to inhibit mTORC1 and thereby promote cellular autophagy, whereas REDD‐1 gene‐product induced mTORC2 to ensure cellular survival. 5 Further, AATF protein has the ability to inhibit the p53‐dependent transcriptional expression of pro‐apoptotic genes such as, Puma, Bax, and Bak. 10 Keeping in view all the above‐mentioned findings, the present study attempts to resolve as to how tumorigenic PVT‐1 gene locus is governed by miR‐2909 RNomics involving effector crucial genes such as, KLF4, AATF, c‐Myc, P53, Deptor, mTORC1, STAT3, and their interplay in terms of mutual regulation. 2 | MATERIALS AND METHODS 2.1 | Archetype cellular models employed Three cellular models with following traits were employed in the pres- ent study: 1. HeLa cervical cancer cells that exhibit no intrinsic miR‐2909 expression. 2. Prostate cancer cells (PC3) that exhibit high intrinsic miR‐2909 expression. Abbreviations: PVT‐1, Plasmacytoma variant translocation; AATF, Apoptosis antagonizing transcription factor; KLF4, Krupple like factor 4; DEPTOR, DEP domain‐containing MTOR‐interacting protein; mTORC1, Mammalian target of rapamycin complex 1; STAT 3, Signal transducer and activator of transcription 3; REDD1, Regulated in development and DNA damage responses 1 Received: 24 May 2018 Accepted: 18 September 2018 DOI: 10.1002/cbf.3360 Cell Biochem Funct. 2018;1–5. © 2018 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/cbf 1