This review introduces recent observations regarding (i) metabolic reprogramming of the α-KG balance by IDH mutation and hypoxia in cancers, (ii) the tumor-suppressive functions of the cancer driver genes JARID1C/KDM5C and UTX/KDM6A, and (iii) mutations in genes encoding other isoforms in various cancers, namely, JARID1A, 1B, 1D, and JMJD3/KDM6B of the KDM5 and KDM6 subfamilies. The gene discussed is KDM5C; the disease is cancer.