Noncoding RNA as an influential epigenetic modulator with promising roles in cancer therapeutics.

The epigenetic landscape has an important role in cellular homeostasis and its deregulation leads to cancer. Noncoding (nc)RNA networks function as major regulators of cellular epigenetic hallmarks via regulation of vital processes, such as histone modification and DNA methylation. They are integral intracellular components affecting multiple oncogenic pathways. Thus, it is important to elucidate the effects of ncRNA networks on epigenetic programming that lead to the initiation and progression of cancer. In this review, we summarize the effects of epigenetic modification influenced by ncRNA networks and crosstalk between diverse classes of ncRNA, which could aid the development of patient-specific cancer therapeutics targeting ncRNAs, thereby altering cellular epigenetics.

Sequence driven interaction of amino acids in de-novo designed peptides determines c-Myc G-quadruplex unfolding inducing apoptosis in cancer cells.

c-MYC proto-oncogene harbors a putative G-quadruplex structure (Pu27) at the NHEIII1 domain, which can shuffle between transcriptional inhibitor quadruplex and transcriptionally active duplex. In cancer cells this quadruplex destabilization is preferred and NHEIII1 domain assume a duplex topology thereby inducing c-MYC overexpression and tumorigenesis. Hence, the c-MYC quadruplex acts as an excellent target for anti-cancer therapy. Though researcher have tried to develop G-quadruplex targeted small molecules, work with G-quadruplex targeting peptides is very limited. Here we present a peptide that can bind to c-MYC quadruplex, destabilize the tetrad core, and permit the formation of a substantially different structure from the quartet core seen in the canonical G-quadruplexes. Such conformation potentially acted as a roadblock for transcription factors thereby reducing cMYC expression. This event sensitizes the cancer cell to activate apoptotic cascade via the c-MYC-VEGF-A-BCL2 axis. This study provides a detailed insight into the peptide-quadruplex interface that encourages better pharmacophore design to target dynamic quadruplex structure. We believe that our results will contribute to the development, characterization, and optimization of G-quadruplex binding peptides for potential clinical application.

Curcumin arrests G-quadruplex in the nuclear hyper-sensitive III1 element of c-MYC oncogene leading to apoptosis in metastatic breast cancer cells.

c-MYC is deregulated in triple negative breast cancer (TNBC) pointing to be a promising biomarker for breast cancer treatment. Precise level of MYC expression is important in the control of cellular growth and proliferation. Designing of c-MYC-targeted antidotes to restore its basal level of cellular expression holds an optimistic approach towards anti-cancer treatment. MYC transcription is dominantly controlled by Nuclear Hypersensitive Element III-1 (NHEIII1) upstream of the promoter region possessing G-Quadruplex silencer element (Pu-27). We have investigated the selective binding-interaction profile of a natural phytophenolic compound Curcumin with native MYC G-quadruplex by conducting an array of biophysical experiments and in silico based Molecular Docking and Molecular Dynamic (MDs) simulation studies. Curcumin possesses immense anti-cancerous properties. We have observed significantly increased stability of MYC-G Quadruplex and thermodynamic spontaneity of Curcumin-MYC GQ binding with negative ΔG value. Transcription of MYC is tightly regulated by a complex mechanism involving promoters, enhancers and multiple transcription factors. We have used Curcumin as a model drug to understand the innate mechanism of controlling deregulated MYC back to its basal expression level. We have checked MYC-expression at transcriptional and translational level and proceeded for Chromatin Immuno-Precipitation assay (ChIP) to study the occupancy level of SP1, Heterogeneous nuclear ribonucleoprotein K (hnRNPK), Nucleoside Diphosphate Kinase 2 (NM23-H2) and Nucleolin at NHEIII1 upon Curcumin treatment of MDA-MB-231 cells. We have concluded that Curcumin binding tends to drive the equilibrium towards stable G-quadruplex formation repressing MYC back to its threshold-level. On retrospection of the synergistic effect of upregulated c-MYC and BCL-2 in cancer, we have also reported a new pathway [MYC-E2F-1-BCL-2-axis] through which Curcumin trigger apoptosis in cancer cells.Communicated by Ramaswamy H. Sarma.

Targeting Ca2+ signaling: A new arsenal against cancer.

The drug resistance of cancer cells is a major concern in medical oncology, resulting in the failure of chemotherapy. Ca2+ plays a pivotal role in inducing multidrug resistance in cancer cells. Calcium signaling is a critical regulator of many cancer hallmarks, such as angiogenesis, invasiveness, and migration. In this review, we describe the involvement of Ca2+ signaling and associated proteins in cancer progression and in the development of multidrug resistance in cancer cells. We also highlight the possibilities and challenges of targeting the Ca2+ channels, transporters, and pumps involved in Ca2+ signaling in cancer cells through structure-based drug design. This work will open a new therapeutic window to be used against cancer in upcoming years.