Fig. 4

Schematic diagram of the different roles for epigenetic therapeutic targets in LSCC. a A recent study suggested that NSD3, the neighboring gene of FGFR1, rather than FGFR1, was the critical driver oncogene within this recurrent focal amplicon of 8p11-12 genomic region. The amplification of NSD3 leads to increased NSD3 expression, thus increasing the synthesis of H3K36me2. Less common than the amplification of 8p11-12 and NSD3 expression, the GOF variant NSD3 was also present in LSCC. These two works together to increase H3K36me2, stimulating transcription of oncogenic targets, including mTOR pathways and MYC-associated pathways. This process rendered the tumor NSD3-addicted, which could be inhibited by BETi. b SOX2 and BCL11A are both identified as LSCC oncogenes. The BCL11A-SOX2 transcriptional program is crucial for the maintenance of a squamous phenotype. SETD8 is a monomethyltransferase, whose gene is regulated by SOX2 and BCL11A. The inhibition of SETD8 selectively limits LSCC tumor growth. c LSD1 could promote tumorigenesis in two different ways. The first way is demethylase-dependent. In SOX2-expressing tumor cells, LSD1 inhibition will induce increased H3K9me1/me2. The repressive H3K9 methylations act on the SOX2 gene, leading to SOX2 downregulation, reduced oncogenic potential, and increased cellular differentiation. The second way is demethylase-independent. In cells with a low level of LSD1, FBXW7 forms a dimer, which promotes ubiquitylation for proteasomal degradation of oncoprotein substrates, thus suppressing cell outgrowth. In cancer cells with overexpressed LSD1, the FBXW7 dimerization is blocked by LSD1 binding to FBXW7 in a demethylase-independent manner. FBXW7 self-ubiquitylation will then be triggered, followed by degradation by proteasome as well as lysosome in a p62-dependent pathway. d EZH2 is an enzymatic subunit of PRC2, which also includes EED, SUZ12, and RBBP4/7. The SET domain of EZH2 is responsible for the catalyzes the mono-, di-, and trimethylation of H3K27 from the universal methyl donor SAM, after which SAM becomes SAH. EZH2 also has noncanonical functions with its hidden TAD. The EZH2 TAD directly interacts with cMyc and other activators, including p300 and SWI/SNF. GOF gain-of-function, PRC2 polycomb repressive complex 2, SAH S-adenosyl-l-homocysteine, SAM S-adenosyl-l-methionine, TAD transactivation domain