The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

Histone deacetylases (HDACs) are important regulators of gene expression. Specific structural features and distinct regulative mechanisms rationalize the separation of the 18 different human HDACs into four classes. The class II comprises a heterogeneous group of nuclear and cytosolic HDACs involved in the regulation of several cellular functions, not just limited to transcriptional repression. In particular, HDAC4, 5, 7 and 9 belong to the subclass IIa and share many transcriptional partners, including members of the MEF2 family. Genetic studies in mice have disclosed the fundamental contribution of class IIa HDACs to specific developmental/differentiation pathways. In this review, we discuss about the recent literature, which hints a role of class IIa HDACs in the development, growth and aggressiveness of cancer cells.

The MEF2-class IIa histone deacetylase (HDAC) axis operates in several differentiation pathways and in numerous adaptive responses. We show here that nuclear active HDAC4 and HDAC7 display transforming capability. HDAC4 oncogenic potential depends on the repression of a limited set of genes, most of which are MEF2 targets. Genes verified as targets of the MEF2-HDAC axis are also under the influence of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that affects MEF2 protein stability. A signature of MEF2 target genes identified by this study is recurrently repressed in soft tissue sarcomas. Correlation studies depicted two distinct groups of soft tissue sarcomas: one in which MEF2 repression correlates with PTEN downregulation and a second group in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of MEF2-HDAC interaction shows additive effects on the transcription of MEF2 target genes and on sarcoma cells proliferation. Overall, our work pinpoints an important role of the MEF2-HDAC class IIa axis in tumorigenesis.

SUMMARY The connection between signaling pathways activating cancer associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses gene expression program(s) leading to stromal senescence and CAF activation. Deregulated Gli signaling can also contribute to CAF conversion. Here we report that compromised CSL function depends on Gli activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL up-regulates the expression of the Ulk3 kinase, which binds and activates Gli2. Increased Ulk3 also induces autophagy, which is unlinked from Gli and CAF activation. Ulk3 up-regulation occurs in CAFs of several tumor types and Ulk3 silencing suppresses the tumor enhancing properties of these cells. Thus, Ulk3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention