The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors

WHSC1 is involved in DNA damage, cellular senescence and immune response in hepatocellular carcinoma progression

“…It is well known that DNA damage repair pathways is correlated with variability in HCC clinical outcomes. WHSC1 specifically catalyses H3K36me2, which will result in conformation of chromatin, transcriptional regulation to control cell growth, DNA damage and apoptosis in several cancers 4 . It has been reported that WHSC1‐mediated di‐methylation of PTEN at K349 is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA damage sites and result in dephosphorylation of γH2AX for governing efficient repair of DSBs 8 …”

“…DDR status has been confirmed to serve as a potential biomarker to predict opposite clinical prognosis of immunotherapy. WHSC1 encodes a SET domain‐containing histone methyltransferase, which could catalyse the di‐methylation of H3K36 to involve in gene transcriptional regulation 4 . However, further study is necessary for the function and carcinogenic mechanism of WHSC1 in HCC.…”

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

“…As we mentioned earlier, NSD2 is a promising therapeutic target, and its translocation, mutations, and overexpression are closely associated with the proliferation, migration, and invasion of cancer cells. ,− However, developing small-molecule inhibitors targeting the catalytic SET domain has yielded little success. , Recently, a selective covalent NSD1 inhibitor 30 (BT5) and two specific NSD2 inhibitors 11 (LEM-14) and KTX-1001 ( Identifier: NCT05651932) that target the catalytic SET domain have been identified. , Among previously reported NSD inhibitors, 30 (BT5) and 11 (LEM-14) are the first inhibitors selectively targeting NSD1 and NSD2, respectively. Other than the catalytic SET domain, NSD2 also possesses multiple PPI domains, including PHD domains and PWWP domains (PWWP1 and PWWP2), , which may be clinically relevant and selectively blocked by small molecules (Figure ).…”

“…Hyperactivation of NSDs, including NSD1, NSD2, and NSD3, caused by either overexpression or point mutations, has been reported to be tightly associated with the occurrence and progression of diverse cancer types, ,− including hematological malignancies, such as MM, ALL, etc ., and solid tumors, such as colon cancer, breast cancer, lung carcinoma, etc . , Overexpression of NSD2 in MM patients contributes to tumor proliferation, dissemination, progression, and rapid relapses . NSD2 is one of the most frequently mutated epigenetic regulators in some different cancer types, especially pediatric cancers, such as ALL .…”

“…NSD2 is aberrantly overexpressed, amplified, or somatically mutated in multiple types of cancer and has been defined as an oncoprotein. − Notably, NSD2 is overexpressed in multiple myeloma (MM) patients, predominantly harboring a t­(4,14) translocation that leads to the aberrant upregulation of this gene. − A recurrent gain-of-function mutation with the substitution of glutamic acid to lysine at residue 1099 (p.Glu1099Lys, p.E1099K) in the catalytic SET domain of NSD2 has been revealed in pediatric acute lymphoblastic leukemia (ALL) patients. NSD2 p.E1099K hyperactivates its methyltransferase activity, driving oncogenesis and progression. − Accumulating evidence indicates that NSD2 is overexpressed in various cancers such as MM, skin, lung, bladder, brain, metaplastic breast, and prostate cancer (PCa). ,− NSD2 has been identified as a promising drug target, receiving more and more attention from both academia and the pharmaceutical industry. , Therefore, developing potent and selective small-molecule NSD2 inhibitors may provide potential novel therapies for patients carrying NSD2 overexpression, translocation, and/or mutation. Such compounds may also serve as useful pharmacological tools for exploring the critical roles of NSD2 in various human diseases.…”