Fig. 6 |. Loss of SETD2-mediated H3K36me3 sensitizes cancer cells to inhibition of the FACT complex.

a, H3K36me3⁻ and H3K36me3⁺ (SETD2ΔN-transduced) JHRCC12 cells as well as CAKI-2 cells transduced with the indicated sgRNAs were treated with the FACT complex inhibitor CBL0137 at the indicated concentrations. Cell death was quantified by annexin-V staining (mean ± s.d., n = 3 independent experiments). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (two-tailed unpaired Student’s t-test). b, JHRCC12 cells infected with control retrovirus or retrovirus expressing SETD2ΔN_R1625C or SETD2ΔN_WT were treated with CBL0137 at the indicated concentrations. Cell death was quantified by annexin-V staining (mean ± s.d., n = 3 independent experiments). **, P < 0.01; ****, P < 0.0001 (two-tailed unpaired Student’s t-test). c, JHRCC12 cells infected with control retrovirus or retrovirus expressing SETD2ΔN were untreated or treated with CBL0137 (2 μM) and assessed by the indicated immunoblots. d, NSG mice bearing patient-derived VHL^MTPBRM1^MTSETD2^MT ccRCC xenografts (JHRCC12, JHX3 and JHX491) were treated with vehicle or CBL0137 (60 mg/kg, twice weekly). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (Multiple t-test, Sidak-bonferroni). e, NSG mice bearing patient-derived VHL^MTPBRM1^MTSETD2^WT ccRCC xenografts (JHRCC228) were treated with vehicle or CBL0137 (60 mg/kg, twice weekly). *, P < 0.05 (Multiple t-test, Sidak-bonferroni). f, A schematic summarizing the tumor suppressor model of SETD2 in kidney cancer metastasis. In panels d, e: n = number of mice.