Emerging roles of Myc in stem cell biology and novel tumor therapies

Abstract

The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a “double-edged sword” promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger “awakening” of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…Moreover, the oncogene Myc, which includes c-Myc, N-Myc, and L-Myc, plays an important role in aerobic glycolysis in HCC as well. C-Myc is reported to overexpressed in HCC, and can promote the Warburg effect by increasing the expression of glycolytic related markers, such as GLUT1, LDH and PKM2 [66][67][68][69]. Conversely, c-Myc can also be regulated by PKM2 in the nucleus, for PKM2 can translocate into nucleus and act as a coactivator of β-catenin to induce c-Myc expression, leading to the expression of c-Myc targeted genes [30,67].…”

RETRACTED ARTICLE: A novel positive feedback loop of linc02042 and c-Myc mediated by YBX1 promotes tumorigenesis and metastasis in esophageal squamous cell carcinoma

“…This notion was confirmed by the RIP assay in which linc02042 knockdown substantially decreased the binding of YBX1 to c-Myc 3′-UTR. c-Myc is a well-known oncogene that activates a variety of oncogenic signaling pathways [24]. c-Myc is shown to be frequently overexpressed in multiple cancers, and its expression is tightly controlled by different factors at the transcription or post-transcription level [25].…”

MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells

“…After DLL1-mediated activation of NOTCH1, the intracellular domain of NOTCH1, translocates into the nucleus and binds to the promoter region of the transcription factor RBPJK, which regulates c-myc expression [45]. Given the critical importance of C-myc in prostate cancer [56,57] stem cell self-renewal, maintenance, survival [58,59] and MDR1 expression [38], it is apparent that MDA-9-mediated C-myc expression are major contributors to the PCSC phenotype.…”

“…The importance of C-myc in prostate cancer has been established [56,57]. Recently, the role of C-myc in stem cell self-renewal, maintenance, and survival [58,59] has being emphasized. To confirm whether MDA-9 contributes to C-myc regulation in PCSCs, we analyzed its expression in shcon and shmda-9-treated PCSCs.…”