Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation.

Role of histone acetyltransferases MOF and Tip60 in genome stability.

Cells maintain homeostasis in response to environmental stress through specific cell stress responses. Hypoxic stress, well known to be associated with diverse solid tumors, is one of the main reasons for cancer‐related mortality. Although cells can balance themselves well during hypoxic stress, the underlying molecular mechanisms are not well understood. The enhanced appreciation of diverse roles played by noncoding transcriptome and epigenome in recent years has brought to light the involvement of noncoding RNAs and epigenetic modifiers in hypoxic regulation. The emergence of techniques like deep sequencing has facilitated the identification of large numbers of long noncoding RNAs (lncRNAs) that are differentially regulated in various cancers. Similarly, proteomic studies have identified diverse epigenetic modifiers such as HATs, HDACs, DNMTs, polycomb groups of proteins, and their possible roles in the regulation of hypoxia. The crosstalk between lncRNAs and epigenetic modifiers play a pivotal role in hypoxia‐induced cancer initiation and progression. Besides the lncRNAs, several other noncoding RNAs like circular RNAs, miRNAs, and so forth are also expressed during hypoxic conditions. Hypoxia has a profound effect on the expression of noncoding RNAs and epigenetic modifiers. Conversely, noncoding RNAs/epigenetic modifies can regulate the hypoxia signaling axis by modulating the stability of the hypoxia‐inducible factors (HIFs). The focus of this review is to illustrate the molecular orchestration underlying hypoxia biology, especially in cancers, which can help in identifying promising therapeutic targets in hypoxia‐induced cancers.

Molecular regulation of hypoxia through the lenses of noncoding RNAs and epitranscriptome

SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition

New insights into the DNA repair pathway choice with NuA4/TIP60.

The XPF-ERCC1 heterodimer is a structure-specific endonuclease that is essential for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair in mammalian cells. However, whether and how XPF binding to ERCC1 is regulated has not yet been established. Here, we show that TIP60, also known as KAT5, a haplo-insufficient tumor suppressor, directly acetylates XPF at Lys911 following UV irradiation or treatment with mitomycin C and that this acetylation is required for XPF-ERCC1 complex assembly and subsequent activation. Mechanistically, acetylation of XPF at Lys911 disrupts the Glu907-Lys911 salt bridge, thereby leading to exposure of a previously unidentified second binding site for ERCC1. Accordingly, loss of XPF acetylation impairs the damage-induced XPF-ERCC1 interaction, resulting in defects in both NER and ICL repair. Our results not only reveal a mechanism that regulates XPF-ERCC1 complex assembly and activation, but also provide important insight into the role of TIP60 in the maintenance of genome stability. The XPF-ERCC1 heterodimer is an endonuclease involved in nucleotide excision (NER) and interstrand crosslink (ICL) repair in mammalian cells. Here, the authors provide insights into its regulation by revealing that TIP60 regulates XPF-ERCC1 complex assembly and activation.

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Chun Zhou

Papers

Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation.