HDAC3 regulates senescence and lineage specificity in non-small cell lung cancer

Abstract

SummaryTranscriptional deregulation is a common feature of many cancers, which is often accompanied by changes in epigenetic controls. These findings have led to the development of therapeutic agents aimed at broad modulation and reprogramming of transcription in a variety of cancers. Histone Deacetylase 3, HDAC3, is one of the main targets of HDAC inhibitors currently in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we define the role of HDAC3 in two genetic engineered models of the most common subtypes of Kras-driven Non-Small Cell Lung Cancer (NSCLC), KrasG12D, STK11−/− (KL) and KrasG12D, p53−/− (KP), where we found that HDAC3 is strongly required for tumor growth of both genotypes in vivo. Transcriptional profiling and mechanistic studies revealed that HDAC3 represses p65 RelA/NF-kB-mediated induction of the Senescence Associated Secretory Program (SASP). Additionally, HDAC3 was found to cooperate with the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. Leveraging observations about one HDAC3/NKX2-1 common target, FGFR1, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras mutant cancer cells develop resistance to the MEK inhibitor Trametinib, and this can be rescued by treatment with the Class I HDAC inhibitor Entinostat. These unexpected findings reveal new roles for HDAC3 in proliferation control in tumors in vivo and identify specific therapeutic contexts for the utilization of HDAC3 inhibitors, whose ability to mechanistically induce SASP may be harnessed therapeutically.

NCOR1 Sustains Colorectal Cancer Cell Growth and Protects against Cellular Senescence

“…De-repression of each of these single genes, also associated with SASP, was observed in our NCOR1-depleted CRC cell lines (Table 2). A recent report showed that HDAC3 was required for non-small cell lung cancer cell tumorigenic growth, while central to the repression of p65 RelA/NF-κB-mediated induction of SASP in these cells [46]. Thus, our study is the first to functionally associate NCOR1 with cellular senescence, a process that most likely involves HDAC-associated repressive activities.…”

MAPK11 (p38β) is a major determinant of cellular radiosensitivity by enhancing IR-associated senescence

“…MAPK11 has been found to protect from oxidative stress-induced cytotoxicity in brain [79], muscle [80] and cardiomyocytes [81]. Interestingly, histone deacetylase HDAC3 interacts directly with MAPK11 supressing its transcription activity [82], and this HDAC has been recently proposed as a key regulator of Senescence Associated Secretory Phenotype (SASP) [83]. However, the molecular mechanisms by which MAPK11 manages the induction of senescence in response to IR remains unexplored.…”

“…In addition, other possibilities should be considered. For example, the histone deacetylase HDAC3, which has been recently proposed as a key regulator of Senescence Associated Secretory Phenotype [73], is known to interact with MAPK11 [74], supressing the transcriptional activity of ATF-2. Interestingly, ATF-2 is known to promote survival and efficient DNA repair after IR exposure [75] that could render radioresistance [76,77].…”

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“…The long latency periods for the development of LSCC in GEMMs (7-9 months) significantly hampers preclinical testing of immunotherapies. Additionally, cell lines derived from the primary murine tumors do not always grow in culture to enable transplantable syngeneic tumor models, presumably due in part to p53-activation dependent growth arrest, and require subsequent steps of artificial immortalization with SV40 T-antigen [5].…”